Midazolam Augmentation of Lumbar Steroid Injections – Use, in Just Mechanical Back Pain

Recent article demonstrated that a combination of steroid and midazolam worked well for post herpetic neuralgia:
Miracle Treatment – Low Back Post Herpetic (Post Shingles)Neuralgia Treated With Epidural Steroid and Spinal Midazolam Without Local Can Give Significant Relief For Over 3 Months

This reminded me of an old article finding midazolam alone intrathecally worked as well as steroid (Depo_Medrone 80 mg)epidurally for mechanical back pain… Might the combo, sufficiently diluted for safety, be useful in chronic back pain epidurally or caudally?

Intrathecal midazolam for the treatment of chronic mechanical low back pain: a controlled comparison with epidural steroid in a pilot study
Juliet M. Serrao I, Ray L. Marks ‘, Stephen J. Morley ’ and Colin S. Goodchild
Pain 48 (l992) 5- 17

  • 80 mg prednisolone (Depo Medrone. Upjohn) suspended in IO ml normal saline injected into the lumbar epidural space through an I8 gauge Tuohy needle
  • 2 mg midazolam dissolved in 3 ml 5% dextrose injected into the lumbar intrathecal space
  • Neither had any local injected

Results:

Either will bring down pain scores from 61/100 to 45/100 a 16 point drop – about 1/4 better

The recent article on postherpetic neuralgia found the combo of midazolam and steroid got better results:
Miracle Treatment – Low Back Post Herpetic (Post Shingles)Neuralgia Treated With Epidural Steroid and Spinal Midazolam Without Local Can Give Significant Relief For Over 3 Months
Midazolam had a checkered past with early studies of high concentrations injected in rats and rabbits showing some neurotoxicity:
Reg Anesth. 1995 Sep-Oct;20(5):426-34.
Chronic subarachnoid midazolam (Dormicum) in the rat. Morphologic evidence of spinal cord neurotoxicity.
Svensson BA, Welin M, Gordh T Jr, Westman J. Paediatr Anaesth. 1997;7(5):385-9. abstract here

“Chronic subarachnoid administration of a commercially available preparation of midazolam. After daily injections of 100 micrograms of midazolam” – NO CONTOL GROUP – and from below Schoeffler 1991 we know that a chronic catheter can induce histological changes. Also multiple daily injections were done – hardly comparable to current use  POOR STUDY

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Paediatr Anaesth. 1997;7(5):385-9.
Histological changes following epidural injection of midazolam in the neonatal rabbit.
Bozkurt P, Tunali Y, Kaya G, Okar I.   abstract here

dose – “midazolam 250 micrograms.kg-1” ; for a 70 kg man this would be like giving 17.5 mg epidurally – 8 times the 2 mg that could be used – this is not toxicity but a concentration effect.

Pain. 1999 Mar;80(1-2):419-23.
Neurotoxicity of midazolam in the rabbit.
Erdine S, Yücel A, Ozyalçin S, Ozyuvaci E, Talu GK, Ahiskali B, Apak H, Savci N.   abstract here

“0.3 ml 0.9% normal saline solution, 0.3 ml 0.1% midazolam (Roche, Dormicum) or 0.3 ml preservative free midazolam were intrathecally administered. Light and fluorescence microscopy evaluations were performed on transverse spinal cord sections by a neurohistopathologist in a blind fashion. Midazolam and preservative free midazolam treated rabbits showed significant histologic changes in light and fluorescence microscopy. The histologic and vascular lesions with the use of midazolam and preservative free midazolam suggested neurotoxic effects.” Interestingly, they found undiluted spot injection but no different than  preservative free – so toxicity is probably primarily its acidity.

Midazolam is not soluble in water unless ph is buffered adjusted to a pH of 2.9–3.7. Hence undiluted, it would like an acid injection. Interestedly, unbuffered lidocaine Hydrochloride has a similar ph and high 5% concentrations used in spinal lidocaine have neurotoxic enough effects to have been taken off the market in Europe. Yet, diluted can be used spinally.

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Hence any bad results was with a commercial version injected undiluted. As mentioned,, Spinal lidocaine – 5% with 7.5% dextrose – has been found to have neurotoxicity and has been taken off the market in europe – yet the diluted form is used ubiquitously.

Subsequently, there have been animal studies showing no effect:
Eur J Anaesthesiol. 1998 Nov;15(6):695-701.
An investigation of the possible neurotoxic effects of intrathecal midazolam combined with fentanyl in the rat.
Bahar M, Cohen ML, Grinshpoon Y, Kopolovic U, Herbert M, Nass D, Chanimov M.  abstract here
“no significant differences in the histological changes in the neural tissues of these groups, despite repeated application of the test substances”

Reg Anesth. 1991 Nov-Dec;16(6):329-32.
Subarachnoid midazolam: histologic study in rats and report of its effect on chronic pain in humans.
Schoeffler P, Auroy P, Bazin JE, Taxi J, Woda A.  abstract here
“same amount of fibrosis, infiltration, and deformation in the control group (n = 14), which had received only saline, … Therefore, the histologic changes observed in the spinal cord probably are related to the presence of the catheter”

Can J Anaesth. 1994 Feb;41(2):144-8.
Intrathecal midazolam reduces isoflurane MAC and increases the apnoeic threshold in rats.
Schwieger IM, Jorge-Costa M, Pizzolato GP, Forster A, Morel DR.  abstract here
“Light and electron microscopy studies on sections taken from the spinal cord of four animals did not show any morphological changes suggestive of midazolam-induced neurotoxicity when compared with similar preparations obtained from controls.”
Anesthesiology. 1989 May;70(5):780-6.
Intrathecal midazolam and fentanyl in the rat: evidence for different spinal antinociceptive effects.
Serrao JM, Stubbs SC, Goodchild CS, Gent JP.  free article available from here
no reported issues

Anesth Analg. 1999 Sep;89(3):717-20.
Acute phase histopathological study of spinally administered midazolam in cats.
Nishiyama T, Matsukawa T, Hanaoka K.   free article here

“In conclusion, up to 6 h after direct exposure to midazolam, no acute histological damage or inflammatory reaction of the spinal cord was seen in cats. Implications: Spinally administered midazolam, even in large doses, does not cause acute neurotoxicity or inflammation of the spinal cord.”

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Subsequent to these negative studies, a variety of articles have been published on its use:

Both intrathecal:
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Niv D, Whitwam JG, Loh L. Depression of nociceptive sympathetic reflexes by the intrathecal administration of midazolam. Br J Anaesth 1983;55: 541–547.

Goodchild CS, Serrao JM. Intrathecal midazolam in the rat: evidence for spinally mediated analgesia. Br J Anaesth 1987;59:1563–1570.

Bahar M, Cohen ML, Grinshpon Y, Chanimov M. Spinal anaesthesia with midazolam in the rat. Can J Anaesth 1997;44:208–215.

Nishiyama T, Matsukawa T, Hanaoka K. Acute phase histopathological study of spinally administered midazolam in cats. Anesth Analg 1999;89:717–720.

Serrao JM, Marks RL, Morley SJ, Goodchild CS. Intrathecal midazolam for the treatment of chronic mechanical low back pain: a controlled comparison with epidural steroid in a pilot study. Pain 1992;48: 5-12

Adam P. Tucker, Joseph Mezzatesta, Raymond Nadeson, and Colin S. Goodchild
Intrathecal Midazolam II: Combination with Intrathecal Fentanyl for Labor Pain Anesth Analg June 2004 98:15211527  free article here
intrathecal midazolam 2 mg, fentanyl 10 mcg

Adam P. Tucker, Cindy Lai, Raymond Nadeson, and Colin S. Goodchild
Intrathecal Midazolam I: A Cohort Study Investigating Safety
Anesth Analg June 2004 98:15121520; free article here

  • intrathecal midazolam (2 mg).
  • 1,110 patients
  • “did not increase the occurrence of neurologic or urologic symptoms”

Eur J Anaesthesiol. 2008 Apr;25(4):299-306. Epub 2007 Sep 25.
Combination of low doses of intrathecal ketamine and midazolam with bupivacaine improves postoperative analgesia in orthopaedic surgery.
Murali Krishna T, Panda NB, Batra YK, Rajeev S. abstract here

Int J Clin Pharmacol Ther. 1999 Oct;37(10):519-23.
Addition of intrathecal midazolam to bupivacaine produces better post-operative analgesia without prolonging recovery.
Batra YK, Jain K, Chari P, Dhillon MS, Shaheen B, Reddy GM. abstract here

And Epidural and Caudal:
Nishiyama T. The post-operative analgesic action of midazolam following epidural administration.
Eur J Anaesthesiol 1995;12:369–374.

Nishiyama T, Matsukawa T, Hanaoka K. Continuous epidural administration of midazolam and bupivacaine for postoperative analgesia.
Acta Anaesthesiol Scand 1999;43:568–572.

Int J Clin Pharmacol Ther. 2001 Mar;39(3):116-20.
A comparative study of caudal bupivacaine and midazolam-bupivacaine mixture for post-operative analgesia in children undergoing genitourinary surgery.
Mahajan R, Batra YK, Grover VK, Kajal J.  abstract here

Kathmandu Univ Med J (KUMJ). 2008 Apr-Jun;6(2):166-72.
Midazolam for caudal analgesia in children: comparison with caudal bupivacaine.
Pradhan B, Bajracharya GR.  abstract here

J Clin Anesth. 2009 Mar;21(2):113-9.
Addition of midazolam to continuous postoperative epidural bupivacaine infusion reduces requirement for rescue analgesia in children undergoing upper abdominal and flank surgery.
Ghai B, Makkar JK, Chari P, Rao KL. abstract here
“epidural infusion of 0.125% bupivacaine alone (Group B) or with 20 microg/kg/hr midazolam (Group BM) for 12 hours at the rate of 0.2 mL/kg/h”

Comment – The effect of concentrated midazolam was compared in one article to an acid burn – something that could be easily negated by diluting in sufficient saline. There seems significant evidence of its safely in dilute form. If one is concerned, one could easily Ph neutralize with a little sodium bicarbonate injectable, let it precipitate some, and then use with the already precipitated steroid..
There appears precedence for using midazolam caudally or epidurally – a caudal diluted in 10 – 20 mls saline containing precipitate of 1-2 mls worth Kenalog 40 mg/ml (not the supernatant) and 2 mg midazolam. might have an accumulative effect as found in the post hepetic neuralgia case. Patients would receive no block that way but would be some drowsy for 1/2 hour – this seems safe. Subjects should the lie down with the bad side down for 15-30 minutes as found helpful in a recent article:
Steroid Epidurals – Why Some Work And Some Not So Well

Midazolam got a bad name as a Doctor rape drug and should not be used unwitnessed – best have a relative there.

Anyone had any experience with this mix?

Addendum:

For caudal block injections, I now use a mix:
midazolam 5 mg/ml =  0.5ml – measured accurately in a 1 cc syringe
D5W –  13 mls
sodium bicarbonate 8.4% 1 cc (to neutralize midazolam acidity)
1 cc kenalog 40 mg
(found to work as well as 80 mg):
Sciatica Back Epidural or Caudal – 40 mg Steroid as Good as 80 mg

I inject this mix caudally and have them lie with bad side down for 20 minutes (assuming it’s one sided). Goes in fairly easily – also some pressure feeling.  They are drowsy after for 15 minutes or so; I use oximetry so if they become sleepy I can watch their O2 sats – like oxygem levels over 89. Occasionally people feel immediate relief; most it takes a few days or more.Plans need to be made to have  shot repeated in 8-9 weeks otherwise at 10  weeks they will decide nothing works for them….

You do not have to worry about hypotensive effects of local. I have female staff watch female patients so there can be no unnecessary accustations. Comparisons to sterod epidurals – often better!

Any comments?

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