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9 Articles in Volume 6, Issue #2
Assessment and Treatment of Chronic Pain
Clinical Drug Testing for Pain Medicine
Epidural Indomethacin Alternative in Adult Onset Diabetics
Focus on Urine Drug Monitoring
Office-based Treatment of Opioid Physical Dependence
Oxycodone to Morphine Rotation
Pain Care at the End of Life
Tennant Blood Study—Summary Report
The Psychiatric Model of Treating Chronic Pain

Epidural Indomethacin Alternative in Adult Onset Diabetics

Study confirms hyperglycemia resulting from epidural corticosteroid injections in diabetic patients with recurrent post-laminectomy radiculopathy and assesses indomethacin as a suitable alternative to corticosteroids.

Epidural steroid injections have been advocated for the treatment of degenerative disc disease with radiculopathy1 however, in diabetic patients, steroids have been known to produce hyperglycemia.2 In this study, we determine the effects on blood sugar and pain relief in patients with adult onset diabetes having low back pain with radiculopathy that received either methylprednisolone (MTP) or indomethacin (INM) epidurally. Only patients with recurrent post-laminectomy radiculopathy were included in this study.

Methods

Pre- and post-treatment measurements of blood sugar were made in 140 patients between the ages of 32 and 68 years old having recurrent low back pain and signs of unilateral radiculopathy after lumbar laminectomy between January 1999 and March 2003. Previous diagnosis of adult onset diabetes (AOD) had been confirmed in 102 patients. These patients were taking oral antiglycemic medications and were following a regimen of less than 1600 calories/day and were randomly included in groups A,B and C. The other 38 patients (group D) did not have diabetes mellitus. In all subjects, reappearance of degeneration of the same operated—or adjacent—disc and epidural fibrosis were confirmed by magnetic resonance imaging.

The protocol of the study was approved by the Clinical Research Board of both facilities.

After obtaining informed consent, the patients were assigned at random to either group A (38 AOD patients), that received 80mg of MTP; group B (38 AOD patients) that received 1mg of INM; to group C (26 AOD patients) that were given 2mg of INM or to group D (38 non-diabetic patients) given 80mg of MTP. The corticosteroids were diluted in 3 ml of 0.5% bupivicaine. The injections were usually the first epidural injections in a series of 3 or 5 injections.

Measurements of fasting blood sugar were taken in all patients before the epidural injection, and 2, 24, and 48 hours later. Blood samples were taken from the finger tips and processed through the Freestyle Blood Glucose Monitoring System (Thera Sence, Inc. Alameda, CA) that has a 4.8 + 0.9 % coefficient of variation of accuracy.3 No medications were taken by the patients before treatment. The degree and duration of pain relief were determined by the visual analog scale (VAS; scale of 0 to 10) and assessing it before and then two hours after treatment, before the patients were discharged from the facility. Two, 7, and 14 days later, the low back pain levels were obtained by communicating with the patients by telephone. The pain was considered at a “tolerable” level when patients adjudicated a VAS score of less than 4. The results were tabulated and analyzed by the x2 method.

Results

Diabetic patients in groups B, C, having received indomethacin epidurally, had slight to moderately elevated blood glucose levels at fasting. However, for the diabetic patients in group A, having received the corticosteroid methylprednisolone epidurally, the blood sugar levels rose consistently, with averages values being significantly higher (p<0.05), as demonstrated in Table 1.

The control levels of pain, in patients in all groups, was above 7.0 VAS before treatment with the averages for each group shown in Table 1; these values decreased significantly (p<0.05) at two hours and two days after treatment, however only the patients that received MTP 80mg and INM 2mg had average pain reductions below the tolerable level <4,seven days post-treatment. Fourteen days later, the average VAS pain levels, of groups A and C were above 4, but they remained below the average control values. Patients were discharged for home two hours post–injection, soon after the second blood sample was taken. At that time, no significant sensory or motor loss was noted in any patient.

Discussion

For diabetics, the beneficial anti-inflammatory effect of epidural corticosteroids has been tarnished by some of the complications and side effects2,4 appearing usually after prolonged treatment with usual dosages or after high dosages used in relatively short periods of time.5 Most diabetic patients have a tenuous homeostasis that is difficult to maintain. A decreased adrenocorticotropic hormone (ACTH) and plasma cortisol has been noted 45 minutes after the epidural injection of 40mg of triamcinolone, plus 7 ml of 1% lidocaine— yet the blood sugar remained within normal limits in non-diabetic patients.5 A moderate suppression of the hypothalamic-pituitary-adrenal axis (HPA) has also been documented after epidural triamcinolone, lasting at least two to three weeks, and not responsive when challenged by an insulin-induced hypoglycemic stress.6 In diabetic patients, even a single dose of corticosteroids raises blood sugar and alters the patient’s delicate balance.7

Extremely low levels of steroids can be found in venous blood for up to several weeks after epidural,8 but only minimal trace amounts have been found in CSF.9 It has been assumed that most of the “deposteroids” injected extradurally find their way into circulating plasma and hardly any cross the dura and, instead, act mostly upon the inflamed, degenerated discs and nerve roots outside of the dural sac.10

Table 1. Patient Characteristics Prior to Prolotherapy
    Blood Glucose Levels Pain Levels
Percentage of female patients 63%   Post-Treatment   Post-Treatment
Groups Fasting 2 hrs 24 hrs 48 hrs Control 2 hrs 2 days 7 days 14 days
A DIABET MTP 80mg
[38 patients]
137
(+4.5)
186*
(+6.3)*
198*
(+7.4)*
146
(+5.3)
8.6
(+0.9)
0.7*
(+0.04)
0.9*
(+0.06)
3.4*
(+0.7)
5.9
(+1.1)
B DIABET INM 1mg
[38 patients]
129
(+3.6)
138
(+4.1)
126
(+4.7)
104
(+3.6)
9.1
(+1.6)
0.8*
(+0.06)
1.4*
(+0.04)
4.8
(+0.8)
6.6
(+0.8)
C DIABET INM 2mg
[26 patients]
124
(+4.1)
132
(+3.7)
138
(+5.1)
119
(+3.8)
8.2
(+0.7)
0.9*
(+0.02)*
1.2*
(+0.04)
3.2*
(+0.09)
5.4
(+0.62)
D NON-DIAB MTP 80mg
[38 patients]
91
(+5.2)
98
(+6.1)
103
(+4.9)
94
(+5.3)
8.9
(+1.2)
1.1*
(+0.05)
1.6*
(+0.07)
4.2
(+0.1)
6.9
(+0.8)
( ) Numbers in between parentheses represent Standard Deviation
* p<0.05 as compared to control values [ ] numbers in brackets represent the number of patients in each group
Table 1. Mean values of blood glucose and pain levels.

Under stress, hyperglycemia may be difficult to control in AOD patients, as the catabolic effects of stress may not be adequately compensated by the anabolic insulin response, since lower levels of insulin lead to fatty acid liberation from adipose tissue.11 Reductions of plasma cortisol values have been observed after the administration of epidural dexamethasone and did not increase, even when challenged with insulin-induced hypoglycemic stress.7 In some patients with AOD, the tenuous balance achieved can be easily altered with a single dose.5,6 Other potential contraindication for the use of corticosteroids are shown in Table 2.

The moderate hyperglycemia observed, for at least two days following steroid intramuscular injections, in the group A diabetic patients may be caused by insulin resistance that was probably exacerbated by MTP and suggesting a greater demand for endogenous insulin.5,10 Although temporary rises of blood sugar in relatively well controlled AOD may appear superfluous, they may have serious metabolic consequences if they occur repeatedly.12 Kreier et al13 demonstrated that the parasympathetic nerve fibers located in the abdominal and para-abdominal fat pads participate in the release of free fatty acids by reducing the insulin-stimulated uptake of glucose and increase the activity of the hormone sensitive enzyme, lipase. The moderate hyperglycemia noted in the diabetic patients of group A may have been caused by their usual insulin resistance that was probably exacerbated by the epidural steroid injection. The result was a greater demand for endogenous insulin11,14 and precipitating a metabolic disarray that lasted for at least two days. Dysfunction of the autonomic nervous system has been notorious in diabetic patients.15 Further aggravating the sympathetic-parasympathetic systems imbalance may result in an even greater increase of plasma free fatty acid levels, and is indeed a matter of concern.14

Epidural Indomethacin As Alternative to Corticosteroids

Indomethacin, a non-steroidal anti-inflammatory drugs (NSAID’s), in addition to inhibiting cyclooxygenase peripherally, also appears to produce localized hypersensitivity and to liberate prostanoids that sensitize peripheral nociceptor terminals.16 In addition, these compounds have been found to have a definite central anti-nociceptive action without apparent endocrine, sensory, motor, or autonomic side effects.17 The only available parenteral NSAID available in the USA, indomethacin, is packaged in lyophilized powder as 1-(4 chlorobenzyl)-5-methoxy-2methyl-IH-indole-3 acetic acid with a pH of 6.5. This formulation apparently inhibits PGI synthesis and attenuates the nociceptive activity produced by chemical irritants.18 Our preliminary report comparing the efficacy of epidural indomethacin against methylprednisolone showed that 2mg of INM produced similar intensity and duration of analgesia as 80 mg of MTP, whereas 1mg of INM did not, confirming our earlier impression of dose dependant action.19

 
  1. After evidence of side effects from steroids administration
  2. Patients with diabetes mellitus
  3. Patients allergic to steroids
  4. Patients refusing to receive steroids
  5. Patients with chronic congestive heart failure
Table 2. Other contraindications against epidural steroids

The presentation of INM in a lyophilized powder, provides another advantage, in comparison to any suspension of corticosteroids that contain preservatives. Neurotoxicity studies conducted in rats20 and guinea pigs21 with continuous infusions of INM for seven days (20 and 40ug/day), intrathecally, failed to reveal specific injury due to the medication.

Summary

Indomethacin appears to be a reasonable alternative to corticosteroids in the epidural treatment of low back pain and radiculopathy where patient side effects from corticosteroids are anticipated. Because corticosteroids elevate blood sugar in patients with a diagnosis of diabetes, corticosteroids are best omitted in this patient population.

Last updated on: January 30, 2012
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