REPORT ON EFFICACY AND SAFETY OF
EPIDURAL STEROID INJECTIONS FOR A
TYPE 2 VARIAtiON ON KENALOG AND
ADCORTY.DATA SHEETS.
AUTHORS:
DR KEITH BUSH MBBS MD (London.)
DR JOIIN TANNER 'MBBS Bsc, Dip.M-S Med, Dip.Sports Med.
BRITISH INSTITUTE OF MUSCULOSKELETAL MEDICINE
---- -----'• ---------------
BIMM,
27 Green Lane,
' Northwood, Middlesex, HA62PX
DR KEITH BUSH, .
6 Harley Street, London, WINlAA.
DR JOHN TANNER,
Oving Clinic,
Church Lane Oving,
Chicheste
DR KEITH BUSH
CURRICUIUM VITAE
Born Cape Town, South Africa. 23 March 1953
Nationility British
DEGREES:
EDUCATION:
MD BS (London 1978) MD (London 1992)
GMC'Certificate of Specialist Statusl996
1967-1970 Mill Hill Public School
1971-1978 Royal Free Hospital Medical SchoOl, University of London
TUITION FROM:
1979-1981
Dr Iames Cynax, Honoray Consultant in'Orthopedic Medicine St Thontas' Hospital London and visiting ProfCssor in reee6710:51 02/02/2012Orthopaedic Medicine, Universlly of
Rochcster Medical Centre New York. .r-
MAIN RESEARCH:
1982-1995 • The conservative ntanagemeot of $Jllaal dlsordcfS aud lbe path0111orpbological changes which pany their utural resolution•,.:...
MAIN PUBUCATIONS:
A Controlled Study of Caudal Epidural lujectlons of Triamcinolone Plus Procaine Cot lbe Management of IJitractable Sciatica. Spine 16:
572-575, 1991 . .
The Natural History of Sciatica, A Prospective Study with Independent Radiological Review. Spine 17: 1205-1212, 1992
Lower Back Pain and Scilica: How best to manage them. Brit. I Hosp Med Vol 15, No 5: 216-22!. 1994
Back Cue: What to do and When to Refer. Brit I Tber py aud Rellab. Vol 2, No 3: ll27 113'Z, 199
Epidural Inj ctions in lbe Management of Lower Back Pa.io. Lumbar Spine Disorders
Vol 2 Ed: Pro£ Richard Porter, World Scientific. 174-194. 1996
The Outcome of Cer;ical Radiculopathy Treated with P riradlculu/Epidural Corticosteroid Injections:• a Pwspecth•e Study with
Independent Clinical Review. F.uro Spine 1. 5:319-325, 1996
The Pathomorphological Changes That Accompany the Resolution of Cen•ical Radiculopathy: A Pros cti,•e St\ld• with Repeat
Magnetic Resonance Imaging. Spine Vol 22, No 2:183-186, 1997
Conscn•atl\•e Treatment of Cervical Disc Disease. Bai.lliere's Clinical orthopaedics: Cer'\'lcal Disc Deg neration Ed: Professor Sean
Hughes Pub Bailliere Tludall (in press)
i
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MAL'i APPO IME IS:
... •.
1980-to date Orthopaedic Medical Practice
1992-to date Examiner: The Diploma in Musculoskeletal Medicine, Society or Apothecaries
1993-to date Advisory Editorial Board, Spine
199-1 aad 1995 Hoaorary Coaswtaat OrtbopaedJj: Sargeoa
Tbe Royal atioaal Orthopaedic Hospital Tt11st. Loadoa
'...
CURRICULUM VITAE OF DR.JOHN ALBERT TANNER
DOB: 5th May 1952. ADDRESS: Tarigmere Cottage, Tangmere RoadTangmere,
Chichester, West Sussex, P020 6HW. Tel: 01243 773167. PLACE OF BIRTH: Redhill, Surrey. NATIONALITY: British STATUS: Married (3 children). EDUCATION: Eastbourne College- Top Scholarship, London Hospital Medical College. QUALIFICA'IIONS: B.Sc. Psychology 1973 (ULU), MBBS (London) 1977.
,Diploma in Musculoskeletal Medicine l.Q93, Diploma in Sports Medicine 1993, GMC
Registration Number: 2376257. CURRENT EMPLOYMENT: Private practitioner Orthopaedic/Osteopathic and Sports Medicine at: Oving Clinic, Church Lane, Oving, Chichester, West Sussex, P020 6DG. Tel: 01243 773167, Fax: 01243 530567. Staff Grade Rheumatology and Rehabilitation, Salisbury District Hospital, Member of Pain Management Team. Examiner: London Society of Apothecaries, Diploma in Musculoskeletal Medicine. Lecturer: British Institute ofMusculoskeletal Medicine, Modular Courses at Southampton General Hospital for post graduates. London Hospital Diploma Course in Sports Medicine. Chichester and Worthing GP refresher and trainee courses. Orthopaedic Physician:• Hampshire Consta.bulacy and Fire Service on a , consultancy basis. South West Trains, Connex South Central, TRANSCO. Chairman: Physical Medicine Research Foundation - UK. Responsible for organising and lecturing at National and International courses run by the PMRF. Honorary Treasurer: British Institute of Musculoskeletal Medicine. Advisor: To BUPA Clinical Team on Back P'ain Initiative. PREVIOUS EMPLOYMENT: Aug. 1977- Jan. 1978- House physicain to Drs.D.D.Gibbs and Lair, Silver and Mantell, London Hospital. Feb. 1978 - Aug. 1978 - House surgeon to Messers J.L.Grogono and D.W.Cairn, Amersham General Hospital.
Sep. 1978 - March 1979 - Locum GP in various practices in the London area. March
1979- June 1980- Locum SHO (Obstetrics), Royal Bucks Hospital, Aylesbury. June
1980 - July 1981 - Locum casualty officer, Stoke Mandeville Hospital. Aug 1980 - Aug
1981 - GP trainee with Drs.Dooley, Dooley, Holmes, Smith and Thirlwall, 300
Meadowcroft, Aylesbury. Sep 1981 - 1984 .. Part-time assistant to Dr. A. French, Wing, Bucks in General Practice. Sep 1981 - 1988 - Private Practitioner- Orthopaedic Medicine and Sports Medicine. Director of Milton Keynes Sports Injury Clinic. Sep 1985 • 1988 - Medical Advisor to Champneys on Health and Fitness and Orthopaedic edicine. May
1988- Sep 1991 -Orthopaedic Physician, Hamilton, Bermuda, with Dr.H.B.O'Neill, MD, LCOM. Associate Medical Staff, King Edward VII Memorial Hospital, Special procedural privileges in Department of Surgery. RESEARCH EXPERIENCE AND PUBLICATIONS: 1972/73 - Experimental Psychology projects, 1973 .. Research project in Community Psychiatry service atSt.Ciements Hospital, London, Dr.D.Jones•. •
1977 - Leukaemia Project, Royal Marsden Hpspital, Dr.Humphrey Kay. Author of
'Beating Back Pain', Dorling Kindersley, 1987. Several articles published in Journal of
Orthopaedic Medicine. Editorial, British Journal of Therapy and Rehabilitation, 1996.
1
INTRODUCTION
Despite widespread and continued use of epidural steroids for low back pain (LBP) and sciatica for over 40 years recent adverse publicity based on a few case reports of severe neurological sequelae has led to publication of several review articles and re evaluation of the
treatment.
The most notable and extensive evaluation was conducted by the National Health and Medical Research Council of Australia in 1994 from which the authors of this report will be quoting frequently.(!).
The current. problem arises from the recent statement specific recommendation was withdrawn from the Data sheet. Bristol-Myers Squibb made their decision on the lack of evidence for the efficacy of the treatment ,and 5 DAP reports in which triamcinolone acetonide (Kenalog) was implicated in the development of severe adverse reactions, in one case leading to death, within hours or days of epidural steroid administration.
Following a meeting between representatives of the British Institute of Musculoskeletal Medicine and Bristol Myers Squibb in May 1997 it was decided that an Expert Report for a Type II Variation for Kenalog should be presented to the MCA. In the UK as in most other parts of the developed world the use of epidural steroids for LBP and sciatica is practised by a variety of clinicians including rheumatologists, orthopaedic surgeons, pain specialists and musculoskeletal/orthopaedic physicians. The treatment is now available in every District hospital in the UK where such specialists are employed. Furthermore a minority of general practitioners trained in orthopaedic medicine techniques use caudal epidural steroid injections on an outpatient basis. In some centres specially trained physiotherapists are giving this treatment under supervision of rheumatologists.
Depomedrone (methyl prednisolone), manufactured by Upjohn is the steroid most widely used but a sizeable minority have traditionally used triamcinolone acetonide or hexacetonide (Adcortyl, Kenalog, Lederspan). Most of the available literature including controlled studies refers to the use of methylprednisolone and the few case reports of serious adverse reactions tend to involve Depomedrone/Depomedrol.
In this report we are including all published material referring to epidural steroid injections
(E.S.I.) rather than singling out triamcinolone acetonide since the issue revolves around the use I
of corticosteroids as a generic group in this method of treatment There are of course important
distinctions between steroid formulations. in terms of excipients used, which may have a bearing on safety issues, but in terms of therapeutic action in ESI no useful distinctions have yet been made.
HISTORY
Epidural steroids have been used in medical practice since 1952, although the control of spinal pain via caudal epidural local anaesthetic was first intr<;>duced by Sicard in 1901.
ESI have been administered by different routes in different regions of the spine. Most of the literature describes the use of ESI for complaints arising in the lumbosacral spine in which ESI have been given either via the sacral (caudal) or lumbar route. There have been some reports of the use of ESI in the cervical region but this is far less common. In recent. years clinicians
have taken to using ESI via the transforaminal route in the lumbar or cervical region but only uncontrolled studies on this have been published.
'•"
The literature describing ESI use is international, appearing in Italian, French, Belgian, Finnish,
German, Polish, Japanese, Scandinavian, European, English, Australia, New Zealand, Canadian and American literature reflecting the global interest accorded this procedure.
In the last two decades several reviews have been undertaken. These reviews found that with widespread use of ESI the majority of published medical opinion supported their use. Both Corrigan and Bogduk's reviews recognised that intrathecal injections of steroids could result in nerve damage, but referred to the then available literature attesting to the chemical safety of corticosteroid preparations used in the epidural space. Kepes and Duncalf (3) note.that in over 100 reports of ESI over 25 years in which success rates claimed vary from 20% .. 80% no standardised treatment has resulted. Techniques, drugs, criteria for treatment and success differ considerably from one observer to another . Major complications were extremely rare but the rational for the use of ESI had not yet been scientifically proven.
Benzon's reviews in 1985 concluded that ESI result in greater improvement and faster recovery for patients with nerve root irritation. The addition of steroid to an epidural local
anaesthetic or saline gave better results when compared to local anaesthetic or saline alone. Patients with sciatic root irritation of shortr duration fare better. He advised adequate dilution of the steroid in at least 5-10 ml. volume to ensure sufficient spread of the solution to the affected area and to dilute excipients such as polyethylene glycol (used with methylprednisolone). He concluded that the relative safety of ESI was well docwnented but further study should be undertaken to validate the therapy identify the optimun number of injections, the ideal volume, to compare lumbar and caudal approaches in patients both with and without laminectomies, and the difference between saline and local anaesthetic as diluent.
Bogduk's more recent review in 1995 points out that methylprednisolone has a reversible local anaesthetic effect and that the mode of action of ESI has not been put to the test in a prospective study on which inflammation of the nerve roots has been identified befor treatment. He also states that enthusiasm for ESI based on open, uncontro led se rrhie3slJ ot been matched y the results of controlled trials. 'He advocates strongly that . • er ran 6'mised ; controlled studies be undertaken. ••
All review articles concluded that intrathecal steroids are not indicated in the treatment of spinal pain of benign origin due to the known complications arising from repeated or frequent injection (6,7).
RATIONALE FOR ESI
All the causes of pain due to pathology of the s ie have not been clearly established.
Early approaches to pain relief included anaesthetising painful nerve roots, large volume injections which were presumed to have a mechanical or counter irritative effect, and of course, surgery to remove a• protruding disc, osteophyte or more rarely tumour.
Many observations speak against a purely mechanical theory: the lack of correlation between radiological findings and clinical symptoms, the presence of disc protrusions and even large hemiations on MR imaging in the absence of pain, and more recently evidence of an inflammatory component.
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Lindahl.and Rexed biopsied posterior nerve roots during laminectomy. They were found to be inflamed and oedematous, showing proliferative responses (8), •
Olsson (9) caused cervical disc protrusion in dog experiments. He found that the size of the disc
.d the amount of compression were less. important than the accompanying inflammation in
symptomatology. The inflammation changes dynamic factors such as nerve root blood supply, local venous drainage and nerve root mobility. •
The next logical step was to employ corticosteroids in the vicinity of nerve roots to counteract inflammation. Animal studies seemed to confirm the beneficial effects of steroids. Feldman and Behar introduced talcum intracisternally in cats and caused adhesive arachnoiditis and CSF pleocytosis. Intrathecal hydrocortisone pre:vented adhesions• from developing (10). The theory
that this was a direct local eff ct rather thatl.•a systemic one is supported by Lehrer et al. Brain
tissue steroid concentration was studied.. after intracisternal administration of tritiated
methylprednisolone 21-acetate. The white matter attained 5-10 times higher concentrations that those attained by systemic administration of the se dose(11).
Ito was able to show increased capillary permeability re.sulting from inflammation occurred in patients with sciatica. The radiation clearance of Iodine 131 sodium and PSP was accelerated in these patients (12). •
Green et al studied a patient with nerve root swelling caused by a hemiated disc. lrttramuscular dexamethasone caused a reduction in •swelling•••of the. nerve root (shown by myelography)
More recent basic research has demonstrated that nuclear material is toxic to t::terve roots oth in
without a change in size of disc herniation (13).
-I '
(Olmarker 1995). High concentrations of phospholipe A2 (PLA2) are found in herniated
terms of producing inflammation and neurophysiological change (14,15), • Nucleus pulposus
material in the epidural space induces l ucotaxis and an increase in vascular penneability
discs (16) and PLA2 is known . to propagate the inflammatory cascade. with liberation of arachnidonic acid and other mediators such as leukotrienes and prostaglandins (17).
Mononuclear cells are found at• the margin of extruded .discs, These express inflammatory mediators which might induce neovascularisation and persistent inflammation (18).
Corticosteroids are thought to reduce inflammation by inhibiting PLA2 activity. The changes
•I in nerve root morphology and function induced by autologous nuclear material can be reduced
.-.
by intravenous corticosteroids (19) and prednisolone has been shown to afford some protection against nerve degeneration in experimentat' radiculitis (20).
On the basis of the aforementioned •experimental evidenclargely gained from mammalian experiments it seems probable that locally placed steroids may be beneficial.
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Other effects of corticosteroids . include: stabilisation of nerve root membranes by suppressing
ectopic discharges, blocking c
fibre
. transmissionreduction of capillary penneability,
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inhibition of cytokine release from immune cells, reduced migration ..and accwnulation of
lymphocytes, blocking passage . of immune complexes across the base ent membrane, inhibition of prostaglandin synthesis, suppression of superoxide radicals, stabilisation of
lyosomal enzymes at supraphysiologic concentration and inununosuppression of primarily T
rather than B cells. • •• .
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4
BASIC SCIENCE STUDIES
The anti-inflammatory action of corticosteroids is• reasonably well understood and summarised in the preceding section.
As stated previously there are no formal studies which demonstrate beyond doubt the existence of pre-existing inflammatory radiculopathy subsequently treated by BSI which show its' specific mode of therapeutic action in a clinical setting other than by the resolution of symptoms such as pain and im.•.mobility.
In discogenic sciatica diagnosis is principalLy made on clinical signs supported by appropriate
imaging with . the emphasis being on a mechanical cause of nerve root irritation or compression.
Marshall developed an immunofluorescent antibody test to human nuclear glycoproteins and was able to demonstrate a rise in titre in the weeks following an acute mechanical strain of the
lumbar spine in nine cases (21). Unfortunately no formal imaging was obtained to support the
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diagnosis of a disc lesion although most had sciatic root irritation. He argued cogently that '(
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sciatica could be caused by perineural spread of the contents of the nucleus pulposus '(
occurring through an annular rupture without direct mechanical compression. This theory is supported by observers at operation and by discography, (22-24) who noted complete; disc rupture without herniation and the absence of nerve• root compression in many of their cases. Unfortunately there seems to be no further development of sq.ch a test for clinical or experimental. use in the last twenty years. The animal studies by Olmarkt?r (15,19), however; strongly suggest that the degenerating d. isc enzyme ma. trix plays an inflammatory role.
There are no studies on dose-response relationship, optimal dose or conditions of!
. admiriistration..,
There are no studies • on the pharmacokinetics of triamcinolone acetonide or other corticosteroids when given epidurally although there is body of literature on this subject .. when injectable steroids are given intra-articularly or intramuscularly (for which they are licensed). ( See B.M.S.) . •
There is a large body of knowledge on the systemic action and unwanted effects of corticosteroids summarised in the data sheets for Kenalog and Adcortyl. (Appendix 1)
Hypothalamo -Pituitary- Adrenal Axis Suppression
The effect of ESI on the hypothalamo - p tui.tary - adfenal (HPA) axis has been studied (25,26,27). These studies demonstrated that both••methylprednisolone in a dose of 80 mg and triamcinolone acetate (80 mg) caused suppressiO'n of plasma cortisol levels and muting of adrenocorticotrophic hormone response to stimulation for up to 3-4 weeks post injection. The lowest levels were found between the 7th and 14th day after injection. :Since the synacthen test was able to elicit at least a doubling•ofplasma cortisol, it could be arg1:1ed that clinically the,. degree of suppression does not pose any major risk to the patient mounting sufficient response •.: to an acute stress such as surgery. However, it is probable that several ESis, if given at short intervals, may do.
..• •••-- -••••••-'•"•-• •••-••-•--• I
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5
Central Nervous Tissue Uptake
Plasma methyl prednisolone levels were undetectable throughout Jacobs and Pullen's study(21i) .[
indicating that systemic absorption of the steroid is not responsible for the observed HPA axis s'tippression. This agrees with Lehrer's work who demonstrated that when tritiated methyl prednisolone was injected intrathecally in cats direct uptake by the brain was very fast
•whereas absorption into the blood stream was slow because of the high solubility of the
steroid (lt). It is probable that following ESI high concentrations are quickly achieved in the subarachnoid space and r pid absorption by the central nervous tissue follows resulting in HPA suppression. These patients are unlikely to be at risk from other systemic effects of glucocorticoid excess.
See figs. 1,2 from Jacobs and Pullen's article..
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Fig. 1.:
Mean (SEM) 09.00 hours plasma ACTH and cortisol • levels in six patients follO\ving a single extradural injection of
80mg methyl- prednisolone acetate at time 0. None of the patients had received exogenous cortico- steroids for at least 2 months prior to the study. The horizontal dashed line represents the lower limit of detection for the ACTH assay.
Fig. 2.:
Mean .(SEM) 09.00 hours plasma
cortisol in six patients before (I ), 30 minutes after (l\) and 60 minutes after (ij) intra,•enous injection of 250g _ synthetic ACTH betore 1, 7, 14 and 21 days after a single extradural injection
of 80mg methyl prednisolone acetate. -:
None of the patients had received exogenous corticosteroids for at least 2
1)1onths prior to the study.
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6
The effects of ESI on nerves and meninges.
••"' Delaney (2,8) studied the effect of triamcinolone diacetate in a vehicle (polyethylene glycol
3%, _polysorbate 80, benzyl alcohol• 0.9%) and of the vehicle itself in 48 cats after lutnbar epidural injections. Six animals were not injected, 12 had 2% lidocaine, 15 vehicle only with
2% lidocaine, and 15 had 2% lidocaine with 0.7mg/kg triamcinolone diacetate with vehicle. When the animals wet:y sacrificed at 30-120 days, specimens of the spinal root, root exit zone and the meninges at the level of inje tion and level above and below were obtained. Because all the histologic changes were found to be mild it was concluded that local anaesthetic 'steroid
. combinations do not cause significant damage to neural tiss es. 1
Careful scrutiny of this study shows that-2 out of 5 cats sacrificed after 30 days in Group 3 (lidocaine plus 'vehicle') showed meningeal thickening! When these paraffin embedded tissues were sectioned thinner than 1 to 3 urn and studied under light microscopy there was evidence of . arachnoidal proliferation and dural thickening? The occasional presence of rounded and enlarged arachnoid cells in these areas .was considered to be a. signific
•deviation from normal since they are usually flattene.d. .
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In those animals sacrificed and examined after 120 days there was no meningeal thickening or
infiltration in any of the 4 groups. They•.•erroneously concluded that any changes seen at 30 days had largely resolved at 120 days- yet these were different cats. Furthermore,' only 32 cats were examined in total of which 10 were from Group 3. An alternative conclusion might have been that 2 out of 10 cats showed a toxic reaction which may or may not have resolved -
. an incidence of 20%. ! .
The above study used triamcinolone diacetate in vehicle, 2% lidocaine only, lidocainewith vehicle and triamcinolone in vehicle plus lidocaine.
Another stl,ldy by Cicala (29) tested methyl prednisolone with 1% lidocaine, Ringer's solution, and. normal saline and talc (as a positive control) on rabbits injected epidurally.
However, the histologic studies were performed on paraffin embedded tissues sectioned in 4
J..tm thickness studied with light microscopy. All these sections would appear to be thicker than those used in Delaney's study; The study by Cicala is a pilot study and the authors themselves state that _the ''lack of changes in this series certainly does not preclude the 9 possibility of inflammatory reaction in other speCies or of individual sensitivity to this agent.
'Further studis using other species, multiple injections, and various combinations of medications are needed to ftu,lther evaluate possible toxicity of corticosteroid preparations in the epidural space." These studies, as far as we are aware, have not been done.
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Intraneural injection of steroids.
Mackinnon has shown that a variety of injectable steroids may damage peripheral nentes.• 224 injections were made in 112 male wistar rats into their sciatic nerves either intrafascicularly or extrafascicularly. ive agents were tested:
Dexamethasone (Decadron)
Hydrocortisone sodium succinate (Solucortef) Triamcinolone Acetonide (Kenalog)
•Methylprednisolone Acetate (Depomedrol) Triamcinolone Hexacetonide (Lederspan)
. ----•------- - -- -•--- -- --------••---- -- - - .j
7
Saline (as a control)
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The nerves were examined at 9-12 days and 8 weeks.
Those nerves injected with dexamethasone showed minimal damage while those injected with I
triamcinolone hexacetonide and hydrocortisone showed severe widespread axonal and myelin degeneration 1affecting both large and small fibre populations. Triamcinolone acetonide (Kenalog) and methylprednisolone presented an intermediate picture (30) •
,.•,_ .
Sections of neryes at 8 weeks showed evidence of advanced regeneration regardless of agent
used. This latter occurence is a phenomenon not borne out by clinical experience of patients • with such damage who rarely recover more than partially .if at all. Injections given extrafascicularly caused no such injury pattern.
This study shows a direct neurotoxic effect of certain steroid agents and/or their associated vehiCle when injected intraneurally. BSI are unlikely to cause such damage since the caudal route is safely distant from any large nerve roots and the idline approach .is usually chosen for the lumbar route to avoid paramedian blood vessels and exiting nerves and to enter at a point where the epidural space is most capacious: However, blind' lumbar ESI are recognised to stray from true on occasion and nerve root damage has very occasionally been reported. •
Steroids and the intervertebral disc (SIDT).
Although ESI are unlikely to directly enter the disc space there is a recent study (31) on methylprednisolone acetate intradiscal injections in rabbits of indirect relevance.
Intradiscal steroids have been usd sporadically and by a small number of clinicians since Feffer (165) in 1956 claimed significant benefit in the treatinent of disc herniation. There have been reports of patients developing 'calcification of the disc and epidural space; after administration of SIDT with triamcinolone (Dequesnoy (166), Menkes) (167)..•
Aoki (31) studied Depomedrol and Solmedrol at a dose of 4 mg in the L3-4 and L4-5 discs of rabbits. Saline was injected into the L5-6 disc.
Another group of rabbits was injected with polyethylene glycol mixture (P2G) 30 mg/ml into
L3-4 and P2G 60 mg/ml, 0.1 mls into the L4-5 disc.
Twenty four weeks later histological evaluation showed nucleus pulposus and inner annulus ' degeneration with the presence of matrix vesicles (an indication of primary tissue calcification) in the Depomedrol (acetate) group. No such changes were observed in the Solumedrol (sodium succinate) group or saline controls. All rabbit discs injected !with P2G 11 showed degenerative changes and primary tissue calcification, with loss of intranucleus cell&.
Injectable steroid formulations and their excipients. (See Table 1)
All injectable steroids are preserved with various bacteriostatics, stabilisers, buffers and other preservatives. Although they are often referred to as "inert" or "inactive" ingredients,
Golightly (32) in a thorough medical toxicology review revealed that this is clearly not so. It is
more appropriate to refer to them as pharmacological excipients. '•
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The literature was reviewed by the National Health and Medical Research Council of
Australia (I) in its commissioned report on BSI concerning the following ch mical entities.
F••"o' rmulations
buffers
polysorbates (tweens)
citrates •
ethylenediamine tetra-acetic acid (EDTA) sodium sulphite • ,., polyethylene glycol
benzyl alcohol hydroxybenzoates (parabens)
myristyl gamma picolinium chloride •
benzalkonium chloride phenolic compounds
. The findings were as follows:
Buffers
Only to be used if it can be assured that the nature and concentration• of the agents(s) employed are suitable for contact with the cerebrospinal fluid (33), :No iltrormation :was fotmd on the use of phosphate buffers for intrathecal or epidural injections, /
Polysorbates (tweens)
No reports of adverse effects, and no increase in body temperature when given intrathecally
(34)
Citrates
Induce convulsive activity in mice w en given by spinal injection, possibly by chelating divalent cations in the CSF (35).
EDTA
Induce convulsive activity in mice when given by spinal injection, possibly by chelating divalent cations in the CSF (35). •• •.::. '' ' • •
Sodium sulpltite
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Subarachnoid administration produced .irreversible paralysis in rabbits 36,37.
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I Table 1
The-composition of injectable steroid preparations available in the United Kingdom
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• LEDERSPAN
;
f: ADCORTYL
ll
KENALOG
DEPO-MEDRONE
''5mg/ml
lOmg/ml
15mg/ml
40mg/ml
15mg/ml
40mg/ml •
,.t.,riamcinolone hexacetonide benzyl alcohol } 0.9%.
polysorbate 80 0.2 % . sorbitol solution 70 % water for injeCtion to 100 %
triamcinolone acetonide
benzyl alcohol q
sodium carboxymethylcellulose Tween 80 (polysorbate80) sodium chloride
water for injection
triamcinolone acetonide benzyl alcohol '.i
sodium carboxymethylcellulose Tween 80 (polysorbate80) sodium chloride
water for injection
Methyl prednisolone
Polyethylene glycol !
Myristyl-gamma-picolinium chloride
HYDROCORTISTAB
DECADRON
J
25mg/ml
4mg/ml
Hydrocortisone acetate
Polyethylene glycol < r
Polysorbate 80 I
Sodium carboxymethylcellulose 1:
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Dexamethasone phosphate
Creatinine - stabiliser Methyl para OH benz.oate Propyl para OH benzoate
:Sodium citrate ;
Sodium hydroxide
Sodium metabisulphite
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• Polyethylene. glycol
Allegations of neurotoxicity attributable •to polyethylene glycol (6) have been based on misquotations of studies of propylene glycol . While• related, propylent;' glycol and
'j)olyethylenglycol are not 1he same chemical, but ii.l principle they may have similar toxic effects. Nevertheless,. studies cited to impugn polytpylene glycol .investigated the effects of
80 per cent and 100 per cent concentrations of propylene glycol (38.39) whereas commercial
preparations of corticosteroids (or spinal use contain polyethylene glyco,l in concentrations not greater than 3 per c nt (40). ;Hd • the cited studies investigated more realistic concentrations of the glycol there may . have been grounds for concern. .The extreme concentrations. studied preclude leg timate extrapolation to the use of epidural steroids. In contrast, the one study of 3 per cent polyethylene glycol that as been .conducted found no
impaiqnent of neural function af er 30 minutes application to rabbit vagus nerves (40).
. . .• .
Wood (41), however, 'exposed rat sciatic ' nerves •to weekly injections of either methylprednisolone acetate, the vehicle alone, chloroprocaine 1%, repeated 'dry' needle punctures, or no injection. • • .
Nerves treated with either the steroid or its vehicle showed similar incidence and severity of • patchy d generation, including de111yelination, axonal disorganisation and endoneuria! collagen formation. Lesion severity increased with frequency of injection. Curiously none of the animals howed signs o. f neurologi.cal• d. eficit in ter.ms of m.otor or sensory function. •
The clinical signifiGance •of the e. findings are uncertain but suggest caution with rep ated, closely timed injections with such a•preparation near mixed motor or sensory nerves. .
Benzyl alcolzol
On intrathecal administration bacteriostatic water containing benzyl alcohol is associated with:
• flaccid paraplegia artd demyelination with 5 mL of bacteriostatic water (42)
• flaccid paraplegia from 40mL of normal saline containing 1.5 per cent• benzyl alcohol (43)
• nerve degeneration and paraplegia from 20mL of methotrexate injection• containing 0.9 per cent benzyl alcohol (44)
• flacciparalysis ( 45)
• leg paralysis (46) ' '
Hydroxybenzoates
• neurological damage (paraplegia) (44)
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• neuronal block (paraparesis) (47)
• neurotoxicity, paraparesis (45)
• leg paralysis (46) •
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Myristyl gamma picolinium chloride
No reports. of adverse effects found on its use in intrathecal formulations.
Benzalkonium chloride
No.reports were found of the effects of benzalkonium on peripheral nerves or nerve roots but, in concentrations greater than those found in commercial preparations of steroids used for spinal
injection, benzalkonium has been used experimentally as a neurotoxin in the alimentary tract (48-
50) . .•
Phenolic compounds
Chemical meningitis has occurred and phen:ols may also induce seizures (51)
Other Possible Causes of Meningeal Irritation
As early as 1954, D.C.Moore advised that local anaesthetics administered epidurally should be free of preservativesi. This recommendation is largely adhered to by clinicians but few have been as diligent in regards to the vehicle accompanying the•steroid (53)
A report in the literature was found concerning the use of hydrocortisone sodium succinate (Solu-Cortef) intrathecally (52) which shows the dangers of using the water-soluble preparation due to it causing a rapid ionisation effect in the CSF, which in turn leads toshort term chemical meningitis.
All injectable steroids contain excipients but in much smaller •amounts than those shown to be harmful experimentally and in the above case reports. It is well established that talc and other foreign body materials can lead to arachnoidal proliferation. Hurst investigated the effects of a wide range of chemical types including ionic and non-ionic detergents and quaternary ammonium compounds introduced in small amounts into the CSF of rhesus monkeys. He found that "although the pathological process begins immediately after introduction of the irritant and proceeds steadily to its termination the early stages may be almost or wholly asymptomatic and the clinical picture is then one of severe and progressive signs and symptoms arising after a latent period"(54)
From the available evidence the NHMRC concluded that there was no evidence of any deleterious effect of steroid preparations provided they were injected accurately into the epidural space, but also that none of the commercially available formulations of steroids was free of at i least some potential risk of deleterious effects if they were to be injected deliberately or
inadvertently into the intrathecal space. I
How do d ugs cross the dura?
Many physicians are not aware that there are other routes by which epidurally injected agents may reach the subarachnoid space than by in,advertent puncture.
Shantha and Evans (55) studied the micro and macroscopic relationships of the neural membranes to provide a new basis for re-evaluating the spread and locus of action of epidural anaesthesia.
12
The spinal and root dura are continuous withe peripheral nerve 1:\S neural and perineural connective issue. The perineurium is a continuation of the pia arachnoid' which invests the entire central nervous system. When India ink particles are injected into the subarachnoid space itf the horse's lumbar spine they accumulate in the root subarachnoid.space JUSt proximal to the orsal root ganglion. This is called the ink cuff space and it is here that the arachnoid covering shows some remarkable histological features: . proliferated arachnoid cells form villi which breach the dura mater to varying degrees, some even invading the endothelium of epi ura. venules. This has been demonstrated in several mammals including primates and humans. !Prior
•to this it was thought tliat the •dura was impermeable:• although Usubiaga showed in careful
quantitative studies in 1967, that there was 0 transfer of procaine from epidural to subarachnoid space by some 'diffusion pr cess'. Bromage (170) showed only very little radio actively labelled lidocaine remained in the dura itself, indicating some other mechanism than trans dural diffusion.
The endothelium of arachnoid villi has lipoid pores large enough to allow passage of eythrocytes
67 ll through in addition to CSF.
In :the India ink injections of the subarachnoid space some particles are found over the DRG and
•even distant parts of peripheral nerves. This centrifugal spread is due to the anatomical continuity of central and peripheral membranes. Centripeta1 spread may also occur as shown by Moore with intra neural injection of Methylene blue colourd Efocaine - (it reaches the spinal cord within 2-5 minutes; ' • .
' r
Further evidence for there being a transport mechanism rather than a simple• diffusion proce s
comes from the recent study by Byrod and Olmarker (56). They found Evans blue labelled albumen present in the intraneural capillaries of pig spinal nerve roots one minute after epidur f application.\ Ink angiography de onstrated small venules that connected the epidural vein plexus and the intraneural capillaries. Thihelped to explain previous findings that pidurally applied autologous nucleus pulposus causes focal nerve degeneration in the pig• spinal nerve roots - located in the central fascicles (15). The labelled atbumen was also scattered in numerous capillaries in the DRG.
They conclude the potential barrier properties of the dura/arachnoid seem less than effective for preventing substances in the epidural space from reaching the endoneural space of nerve roots. These demonstrated transport routes may also be related to the mechanisms behind epidural anaesthesia and spinal nerve root infiltration;
Quite clearly• a certain amount of whatever we inject epidurally may reach the subarachnoid space and spinal vasculature system. Therefore, the composition, concentration and osmol 1ity,• of the mixture is very important.
'••,•'..•
COMPLICATIONS
c'ppidural is associated with certain known and potential hazards which need'-to be considered before and during execution of the procedure. Each of the techniques carries unique risks and risks in common. Furthermore, different risks can be attributed to different aspects of the procedure; some relate to.the chemistry of the steroid used,•others to the local anaesthetic used, and others to the act of introducing a needle into the epidural space.
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13
Reported complications of epidural steroid use
The NHMRC (Australia) performed an .extensive analysis!of the cqmplications of ESI1from the 1
'published literature. • The following account draws from this excellent analysis, and further new information is added.
1. INCIDENCE OF COMPLICATIONS
(a) audal epidural steroids
No mention is made of complications in five published studies of caudal epidural steroids (57-61). Others explicitly specify incurring no complications (62-63). One study reports exacerbation of back and leg pain for 24 hours but does not state its iticidence. (64)
The complications which .are reported by authors who specified their incidence are summarised in Table 2. Headache arid dural puncture are the two leading complications, neither of which is ascribable to the' use of steroids. Dural puncture is a technical risk of simply introducing a needle into the epidural space. • The mechanism of headache after epidural steroids is not known. It may relate to undetected dural puncture and. leak of cerebrospinal fluid, or it may in some way be related to the injection of large volumes of fluid into the epidural space and temporarily raising intrathecal pressure.
Table2
The complications of caudal epidural steroids based on the literature that provides sufficient numerical data to calculate incidence
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Author
Number
ofpts Nature
treated
Complications
. Number of cases Incidence
Goebert et al. (66) 113 Procaine sensitivity 1 0.9
Spinal anaesthesia (a) 1 0.9
Cardiac failure (b) 1 0.9
Beliveau (65) 48
Mount (67) 542
Headache 10 21
Increcwed pain 2 0.4
Spinl anaesthesia 1 . '0.2 '•.
(a) implies dural puncture
(b) attributable to fluid tetention caused by the steroids
Because studies differ in the number of patients treated, the observed incidence of various complications vades considerably from study to study, A representative incidence can be i' obtained by determining a weighted mean Incidence which is calculated by dividing the
number of reported cases of the complication by the total number of patients treated in all of the studies that observed .that complication. The results of such calculations are shown in Table 3.
.....
14
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It is evident that the reported complications of caudal epidural s eroids are q ite rare except in the case of headache. The calculated incidence of 21 per cent could be an overestimate because only one small study reported this complication. On the other hand, its incidence could be this high or greater if other authors did not consider headache to be a serious enough complaint to warrant being called a complication and therefore being reported.
Table 3
The weighted mean incidence of complications of caudal epidural steroids.
'"''
Complication
Number of Cases Total Treated
Weighted Mean Incidence (ll) (%)
Headache Dural puncture Spinal anaesthesia
10 48
4 703
2 655
2
0.6
0.3
(a) calculated by dividing the number of cases reported by the total number of patients treated in all the studies noting that complication.
A retrospective survey_ of 47 practitioner' clinical experience of 75,000 caudal ESI based on physicians' recalr"ofmajor complications was conducted by J.Tanner 1995 (68) The majority used preservative free local anaesthetic of varying volume (20-50cc) and 90% used triamcinolone acetonide (Kenalog, Adcortyl). The results are outlined below. (Table 4)
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Complications
15
Table4
Number. of
Cases
Incidence
(%)
Comments
Dural punctures Anaphylaxis Hypersensitivity Prolonged hypertension Skin infection
Epidural abscess
Meningitis
Neurologic complication
Headaches
Severe aggtavation of pain less than 24 hours
(Prolonged aggravation of pain)
more than 72 hours
33.
11
. 9
14
1
4
0
3
1
50
1162
163
0.04
0.01
0.01 o.02
0.005
0.07
0.5-1.6
0.29
(Only one with very poor outcome)
Acute -lower limb paralysis probably due to LA effects. Chronic- multi-level neurological symptoms occurring 7 days later.
One leading to surgery.
Other complications
No fatalities
3
1
4-5
2-3
1
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Worsening chest infections. Diabetes mellitus precipated. Suspected peptic ulcer aggravation. Cushing id changes.
Bizarre symptoms . '
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iQp the basis of this summary it appears that caudal ESI are relatively safe.
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16
No mention is made of complica ions in nine studies of lumbar epidural steroids, (69-77) and a further study by Hickey (78) explicitly stated incurring no complications in 250 patients. Without specifying incidence, several •authors• have reported headache, (79,80) exacerbation of pain, (80-82) • hypotension,(80) fluid retention (66) and dural puncture (83). From those studies that speCify actual incidence,. the complications of lumbar epidural steroids are shown in Table 5. •
•
The weighted mean incidence of complications from lumbar epidural is shown in Table 6
It would seem evident that the incidence of complications from lumbar epidural steroids is appreciably greater than that for caudal epidural steroids; most notably, the incidence of dural puncture is far greater.
In addition to this data drawn• froin clinical studies of lumbar• epidural steroids, the literature contains several case reports of complications. While such case reports provide no insight into the possible inCidence of such complications, they serve to highlight the possibility of certain complications not otherwise• recorded in the literature. These are summarised in Table 7.
....
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Table 5
The complications of lumbar epidural st roids based on the literature that provides sufficient numerical data to calculate incidence.
'•"'
Author Number of Complications: Incidence Patients• Nature Number of (%) Treated Cases
( ' Warr et al. (79) 500 pural puncture 7 1.4
Exacerbated pain 2 0.4
l ! Harley (85) 50 Headache 1 2
. Exacerbated pain 1 2
Ito 12) 296 Headache 17 6
Exacerbated pain
5 2
Swerdlow,
Sayle-Creer (86) 325 Dural puncture 11 3
Ridley et al. (87) 21 Dural puncture 2 9
. Dilke et al. (82) 35 Dural puncture 6 17
Jurmand (88) 3544 Dural puncture 183 5
Headache 33 1
Gilly (89) 50 Dural puncture 2 4
Exacerbated pain 2 4
Berman et al. (89) 367 Hypotension 10
I Difficulty voiding 5
Severe paraesthesiae 4
Angina 1
Sinus arrhythmia 1
Spinal anaesthesia 1
Headache 1
Table 6
The weighted mean incidence of complications of lumbar epidural steroids
. Incidence (a)
(a) calculated by dividing the number of cases reported by the total number of patients treated in all the studies noting that complication.
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Table 7
A list of complications attributed to lumbar epidural steroid injections in case reports
Source Complication
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Shealy (90)
Dougherty and Fraser (91) Abram and Cherwenka (92) Knight and Burnell (25) Stambough et al. (93)
... ,.
Epidural abscess Meningitis Headache. Hypercorticism Hypercorticism
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Gutknecht (94)
Chan and Leung (95) Simon et al. (96) Williamson (97)
Sekel (98)
. Goucke ai1d Graziotti (99)
Intrathecal injection with chemical meningitis
Epidural abscess Allergy to steroid Subdural injection Tethered dural sac Extradural abscess
The complications of lumbar epidural steroids can thence be grouped into:
\ • side effects attributable to the pharmacology of the steroid injected;
, I the effects of adjuvant agents injected;
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•
enigmatic complications;
infection;
dural puncture/intrathecal injection.
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Steroid side-effects
The literature on epidural steroids. mentions very few complications that can be attributed to the chemistry or pharmacology of the steroid injected. Adrenal suppression occurs but is rarely manifest clinically. It is known from several studies that the epidural injection of steroids has an effect of suppressing the secretion of glucocorticoids by the adrenal ghi.nd for about 2-3 weeks (84,26). .. •
No deleterious effects of this suppression have been docwnented, but some authors warn that this should be taken into consideration in patients due to undergo surgery durin'g 'that time period (26). One case of steroid allergy has been reported. Fluid retention leading to congestive cardiac failure has been noted in the literature but appears to be very uncommqn. One investigator has reported minor digestive disturbances and occasional patients with minor changes in serum glucose.(88). Overt endocrinological effects, however, have rarely been encountered with the use of epidural steroids. There have been case reports of .overt steroid side-: effects in the form of Cushingoid hypercorticism (93, 94) but this has usually occurred when extraordinary and inordinate doses have been used (betwen 200 mg and 400 mg of methylprednisolone over one to three days), although one such patient received only two injections of 80 11;1g me hylprednisolone one week apart.
19
Side-effects of other agents
Local anaesthetics anaesthetise small diameter afferent• fibres and sympathetic efferent
••"fibres.
Consequently, when used as an adjunct to minimise the pain of epidural injections of steroids, local anaesthetics can cause side-effects such as spinal anaesthesia and hypotension.
Enigmatic complications
Enigmatic complications of epidural steroids are those without a known or apparent physiological basis. These are headache and temporary exacerbation of sciatic pain.
Analysis of the literature indicates that exacerbation of sciatic pain is related to the injection of large volumes of fluid into the epidural space, and it has been suggested that this symptom can be avoided by injecting slowly.(82)
Headache is a complaint known to be associated with epidural anaesthesia for childbirth and is therefore not a complaint unique to epidural steroids.(lOO) Its mechanism remains obscure. In the context of epidural steroids it may• well be due to unrecognised dural punctllres. In this regard, Jurmand (88) incurred headache in 33 patients in the course of 3544 injections - an incidence of 1 per cent, but these occurred only in the 183 patients who sustained a dural pUncture- an incidence of 18 per cent. Headaches could occur following unrecognised dural puncture as a result of cerebral spinal fluid leakage or as a result of inadvertent injection of air into the subarachnoid space.(92,10l).
. Infection
Infection is a risk of any procedure that involves penetration of the body with a needle, but it is minimised by adherence to strict aseptic technique. Its incidence following lumbar epidural steroids is extremely rare, having been noted only in four case reports (Table 7).
Dural puncture
The most consistently reported and the most common complication of epidural steroids is dural puncture, particularly in the case of lumbar epidural steroids. It should be noted , however, that although the caudal approach is designed to avoid this complication, it nonetheless can occur even with that approach (Tables 3,4). • • •
'
White et al (102) who used radiographic controls in their study pf300 caudal and lumbar•
epidural injections warn of incorrect needle placement. In their study needles were incorrectiy located in 25 per cent of caudal injections and in 30.4 per cent of lumbar injections•. In the
case of caudal injections these incorrect placements included failure to enter the sacral canal and intravascular placement, but dural puncture was never encountered. In the case of lumbar injections penetration of the dural sac occurred 'several times' but the exact incidence was not specified. To some operators well-skilled in epidural techniques these figures appear unduly high,(JoJ, 104) but they do serve to illustrate that incorrect needle placement can occur.
[1 20
f1 In a related study Mehta et al (lOS) studied the accuracy of needle pla ement in the course of 85
Ll lumbar, six thoracic and nine cervical epidural local anaesthetic blocks in 100 patients.. He
encountered inaccurate placements in 17 per cent,\rendered evident by obtaining radiographs
; I ••"' following a test injection of 0.2mL of contrast medium. None of the inaccurate placements,
' . however, involved puncture of the dural• sac. Nine fell short of entering the vertebral canal
and did not even reach the epidural space. One only partially entered the epidural space. On seven occasions the injection was made partially into •the epidural and partially into the subdural space. This study, like that of White et al.. indicates that incorrect needle placements can occur during the execution of epidural injections, but more specifically it demonstrates that under-penetrat on rather than over penetration is more likely.
Inaccurate needle placement also occurs with the caudal approach when used for epidural steroids (106-7) or for epidurography.(tos) In the course of •epidurography :.incorrect needle 11 placement was seen to occur in some 14 per cent ofcases1but the failures involve missing the sacral hiatus or intravascular injection rather than over-penetration.
. '
L '
I To avoid performing injections when needles have peen incorrectly placed, some authors have advocated that epidural steroid injections are best performed under fluoroscopic control (106). White et al. recognised that radiographic control . would not be appealing to all who used epidural steroids, but reported that it had become routine in their own institution.
Abrams and O'Connor (109) in a more recent review note that most of the warnings regarding the potential hazards of ESI are based on complicat.ions following repeated subara_chnoid steroid injections. (6,110 llOa,9l,lll). The relevance of this to the use ofESI is limited. The risk of dural puncture in lumbar ESI is 5% (see •above) and in caudal ESI 0.6% or lower. This represents a complication only in that it is an unintended component of the procedure and of course dural puncture is a routine procedure in neurological practice, (lumbar puncture), radiology (myelography), anaesthetics• (spinal anaesthesia). Some authors (6) have extrapolated this risk to imply that the operator through not recognising he has entered the subarachnoid space proceeds to inject the steroids and local anaesthetic mixture. The greater proportion of dural punctures. are.recognised at the time, so when epidural injection is desired, the procedure is aborted.
Relationship Between Arachnoiditis and Subarachnoid and Epidural Steroids
Abrams and O'Counor (109)
One of the commonly voiced argumeqin favour of the neurotoxicity of intraspinal• steroids is the notion that arachnoiditis does not exist in the absence of some form of i trogenic intervention . Roche (8) for instance, in reference to a group of patients with radiographic evidence of arachnoiditis, states "These patients have had subarachnoid steroid injections a:s either the only procedure or the most likely procedure that could have induced such changes. Adhesive arachnoidits has not been found at this hospital in the absence of some type of
•intervention. However, casual literature search for the spontaneous occurrence • of
arachnoiditis (i.e., without antecedent spinal injections of any sort) yield more than a few references.
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21
In 1972 Ransford and Harries (121) published a report of five patients.exhibiting arachnoiditis at the time of laminectomy in w,P.om "....no predisposing cause of the arachnoiditis other than the disk lesions could be implicated". These patients had not undergone previous
'•myelography or steroid injections. In addition to citation of these cases, the authors presented an extensive review of the previous literature on the occurrence of arachnoiditis and its association with spinal injections, infection, injury, surgery, degenerative lesions of the vertebrae and disc and tumours. Two other referenpes to cases that occurred in conjunction with lumbar disc lesio s are cited (122-3) along with three reports of arachnoiditis accompanying degenerative cervical spine disease (124-6) . There is a fairly extensive list of references to cases of arachnoiditis occurring after spinal surgery (127-31) . One of these references (127) refers to a case of calcific.. arachnoiditis (arachnoiditis ossificans). Many of these cases were reported before the introduction of subarachnoid or epidural steroid injections. Two citations (132-3) referred to cases of arachnoiditis that occurred without any apparent inciting cause. Two cases of arachnoiditis ossificans hi the absence of subarachnoid injections were reported by Wise(B4).
Several more recent reports document the existence of arachnoiditis in the absence of spinal injections Epstein et al. (135) reported five cases of sev:ere obliterative arachnoiditis in partients with spinal stenosis. In all of these cases, araclmoiditis was confirmed at the time of surgery. Only one patient had undergone any type of intraspinal injection, a myelogram that had been done 23 years previously. Brodsky (136), Vloeberghs et al. (37), and Quiles et al. (138), have reported cases of arachnoiditis in patients without previous surgery or spinal injections.
• Duke and Hashimoto (139) reported cases of severe arachnoiditis that occurred spontaneously in six members of the same family.
Much of the evidence • for implicating subarachnoid steroids in the pathogenesis of arachnoiditis comes from cases of multiple sclerosis treated with subarachnoid MPA. While there is little data regarding the incidence of spontaneously occurring arachnoiditis in multiple sclerosis, there are reports of such occurrences.(I40-I).
The fact that arachnoiditis can occur in the absence of subarachnoid injections does not rule out the possibility that such injections can cause arachnoiditis. Indeed, there is a well" accepted relationship between the use of subarachnoid contrast agents such as Pantopaque and Lipiodol and the subsequent development of arachnoiditis (6,54,142,143). However, the relationship between the use of depot/steroids and arachnoiditis is not as clear. On the one hand, there are case reports that raise suspicion of such a causal relationship (110,112,144). Conversely, there have been no experimental data in animals to confirm a relationship between subarachnoid steroid injections and arachnoiditis. In 8 series of such injections involving 358 patients, there was no clinical evidence of arachnoiditis (145,146,72,148,149-51).
It is the• perceived risk of subarachnoid injection which has been the source of much controversy and alarm in relation to the possible development of arachnoiditis following the procedure of epidural injection.
Foremost, it is conspicuous that of the patients reported as suffering arachnoiditis following intrathecal steroids about whom sufficient details have been published, all had undergone multiple injections of steroids or other intrathecal procedures. Of the first two patients reported with arachnoiditis, (112) one had received 23 intrathecal injections of steroids, and the
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22
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other had received five injections and had undergone myelography with •an oil based contrast medium (a known cause of arachnoiditis). Of four cases subsequently reported (113) only one
•-"was detailed. This patient had undergone 16 injections of intrathecal steroids and an oil based I
myelogram. The patient reported by Bemat (110) had undergone 12 injections of intrathecal •I
steroids. 1:he patient reported by Coh(m (111) had undergone four myelograms, four lumbar operations and 14 intrathecal injections of steroids. •
These reports clearly describe excesses and stand in contrast to the reports of the use of intrathecal steroids for multiple sclerosis without complications.(l14-7). Furthermore, and paradoxically, in contrast to intrathecal steroids allegedly causing lumbar arachnoiditis, they have actually been reported as beneficial in the treatment of this same cond;ition.(I18-20).
The lack of evidence of a relationship between epidural steroid •administration and arachnoiditis is quite remarkable. In our review of the literature, we found no case reports
documenting such a relationship and our review. of •64 series of steroid epidurals, which (
included nearly 7,000 patients, failed to reveal a single report of arachnoiditis. (NHMRC 1994) -\-
CONCLUSION
There appears to be little risk of serious complications associated with the use of epidural steroid injections. Animal studies tend to confirm the safety of neuraxial administration of depot steroids. Allegations that the 3% polyethylene glycol vehicle of MPA and other depot steroids is capable of producing neurologic damage appear to be unfounded. The doses of corticosteroids commonly used are capable of producing. adrenal suppression for up to several weeks, and there are occasional reports of cushingoid side effects from the doses of steroids that are usually given. Epidural steroid injections should be used with caution in diabetic patients, who may be at added risk for epidural infections and whose glucose control may be •
•compromised. Because of the immuno.suppression associated with the steroid, aseptic technique should be meticulous.
Essentially all the literature documenting the safety of epidural steroids comes from reports on the use of a small number of injections, usually one to three and with modest doses, usually
40 to 80 mg MPA or 40 mg triamcinolone diacetate. Extrapolation of these data to situations in which these procedures are done repeatedly or in which much higher doses are used is
risky. There are no data to support the safY of this treatment under such circumstances;
There is some evidence that complicati hs can occur following subarachnoid steroid injections. Aseptic meningitis and bacterial meningitis appear to be uncommon but real risks. • Arachnoiditis and conus medullaris syndrome have been reported, but these cases are generally seen after• multiple injections over a prolonged time interval. The possibility that a serious complication will occur after a single accidental subarachnoid steroid injection is probably very low, provided that strict aseptic technique is used and no contraindications, such as history of untreated tuberculosis or fungal disease or recent septic processes, are present.
23
CLINICAL EFFICACY STUDIES ON ESI
••For the purposes of tlus report only ESI studies given by the caudal or lumbar route will be reviewed.
The attraction of the caudal route is that it is easily performed and decreases the risk of inadvertent dural puncture and therefore the possibility of intrathecal injection.
.
The majority. of investigators "have sed methylprednisolone or triamcinolone as the corticosteroid and have mixed either with substantial volumes of local anaesthetic or normal saline.
. The local anaesthetic, which is preservative free, provides a convenient vehicle to increase the volume of the mixture with the added advantage of temporary relief of pain and the onset of numbness or other changes in the appropriate dermatome which serves to indicate correct needle placement.
All uncontrolled studies on caudal ESI have been favourable with respect to benefit. (61,62,66,IS2)
Although encouraging, such reports do not and should not vindicate the use of caudal epidural steroids, for aside from other shortcomings;they offer no control observations. Other studies, however, have provided such data.
Koes et al (ISJ) reviewed the controlled studies on both caudal and lumbar ESI set out in tables below (Table 8).
On reviewing the four studies on caudal ESI there are methodological difficulties. Yates' (S9) report comparing the effects of four different compositions of injection purported to show that the addition of steroid to any base mixture resulted in greater improvements, but insufficient raw data were published to allow this claim to be evaluated critically.
Furthermore his report did not address pain relief but focused on improvement in• straight leg raising (SLR) which seemed to correlate with pain relief.
Matthews (154) found no difference between steroid treated group and placebo at one month, but a significant difference at three months in favour of the steroid group. UnfortUJ;lately insufficient raw data were published for critical evaluation. •
'-.•.
Beliveau's (65) study does not appear to be formally randomised but allocated alternately to steroid plus 0.5% procaine and 0.5% procaine alone. Although there was no difference in the short term (3 months) he found that patients with a long history of severe sciatica (mean 16 months) the inclusion of steroids appeared to show a significant improvement.
"• __
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Table 8
DETAILS OF TRIALS STUDYING HIE EfFICACY OF EPIDURAL STEROID INJECTIONS FOR LOW-BACK PAIN
Authors Epidural sh:roid injection/route Injections Reference tn:atmc:nt(s) Methods Results }
(no. of patic:nts) (n) (n patients) score
Snoek et al. (i) 80 mg (2 ml) methyl prednisolone, lumbar (ii) 2 ml saline (11 = 24) 72 %patients improved after 2 days with regard to LBP: (i) 33"u. (ii)
(81) route (n = 27) 25%; radiating pain: (i) 26o/o, (ii) 13%; sciatic nerve stretdi tokran.:e:
Math..:ws ..:t al. (i) 80 mg (2 ml) methyl prednisolone+ 20 m!
(15-1) bupivacaine (0.125%). caudal route (n = 23)
1-3 (ii) 2 mllignocaine, 67 subcutaneously (n = 34)
(i) 36%, (ii) 25%; subjective improvement: (i) 67"o. (ii) -1:2"•- "o
patients who underwent surgical treatment within 14 ± 6 months atkr treatment: (i) 58%, (ii) 52%. No statistically signiticant dlfterences.
%patients recovered after 1 month: (i) 67%, (ii) 56%. Not stgnificant. After 3 months: (i) significantly more pain-free than (ii). No significant differc:nce.
(73) procaine (I%), lumbar route (11 = 42)
Bush and Hillier
(63)
,• ,..
-i l ... i
(I%)(11 "'31)
significant. Long-term follow-up (about 20 months} showed no significant differences. •
52 weeks: (i) 44, 73, 80; (ii) 63, 65, 74. _
Short-term: (i) significantly better results (pain, SLR}.- Long-term: pain not significantly different. (i) straight leg raise significanlly bettt:r. (no data presented}. . • •
Serrao et al. (i) 10 m!_saline+ 80 mg prednisolone (epiduml) I (pair) (ii) 10 ml saline (epidural)+ 2 52 No. of patients reporting initial improvement and after2 months: (i) 3.
(155) = 3 ml aextrose (5%, i.t.), lumbar route mg midazolam +dextrose 5; (ii) 10, 7. No significant differences for .Pain and activity scores.
(n= 14)
Klenc:rml!n et al. (i) 20 m!saline+ 80 mg methyl prednisolone.
(/56} lumbar mute (11 • • 1 'J)
:• ' I
l; 1 •.•
Dilke c!l al. ( i) 10 ml saline + 80 mg methyl prednisolone.
(lil) lumbar route (n ". 51 )
;•.:
;•,.
4a
1-2
(3 ml, 5o/o, i.t.) (n = 14)
(ii} 20 ml saline (n = 16) 50
(iii) 20 ml bupivacaine (0.25%)
(n= 16)
(iv) dry needling.interspinous ligament (11 = 12)
(ii) I ml saline (n = 48) 50
(ii) significantly less self-administered medications. •
No. ofpatients improved or cured according to clinician:. (i) 15. (ii)
11, (iii} 11, (iv) 10. No signiticant differences.
No. ofpatic:nts not returned to work at 3 months: (i) 3 of36,• (ii) 14tlf
35. Di1Ten.'11cc is significant. N<, difft.."f'cnccs in no. days of hcd re't and days in hospitaL No. of patients r<.-porting none and• itut !><:\ere pain after 3 months: (i) 16, 24; (ii) 8, 20.
Rocco et al.
Ridky cl al.
(i) 50 mg' litnricaine + 75 mg triamcinolone
(157) , (l0.9ml).lumbarroute (n=8)
(ii) 50 mg li h aine + 75 mg triamcinolone + 8
mg morphine (10.9 m1) (n = 7}
(i) I0 m!saline+ 80 mg. methyl prcJnisolonc.
1-3
1-2
(iii) 50 mg lignocaine+ 8 mg morphinc(10.9 ml)(n=7)
(ii) saline (2 ml). interspinous
49
'47
Mean improvement Qn VAS after 1 month: (i) 0.9. ,:(ii) - 0.6 (deterio tion) (iii) 0.4. No. <lfpatients reporting long-tc:m1. rdi.:f: • (il
I,(ii) o. (iii) 0. No significant differences. •
% patients reporting improvement after 2 weeks: (i) 90%(ii) 19 o.
(87) lumbar route (n = 19} ligament(11= 16) Short-term (i) significantly better in relieving pain.
lldiveau (i} 40 ml procaine{0.5%) + 80 mg (2 ml) 1-2 (ii) 42 m!procaine (0.5%) 45 No. of patic:nts improved or completely relieved during 3 months
Yab:s
(65)
methypr nisolone, caudal route (n = 24)
(i) 60 mg trifl.m inolone (3 ml) + 47 ml saline(-} 1-4
(n = 24)
(iii) 50 m!saline H
follow-up period: (i) 18, (ii) 16. No significant difference.
17 (i) and (ii) better than (iii) and (iv) regarding improvement in straight
(59) (ii) 60 mg lriamcinolonc (3 ml) + 47 tit!
lignocaine (0.5%) (-J
(iv) 50 m1lignocaine (0.5%) (-)
let raising. No data on patient level presentc:d.
-.-Rcsuils ot the most important Ol!lcomc m l.o;urcs-accol:-o"""li-igto the-<mtl1(ir -;,ltflc study_ --... --•-•--
p <0.05 were taken as significant.
25
Bush's study (63} appeared to show a significant improvement within the steroid treated group at four weeks on all outcome measures, which did not occur in the placebo group. At one year only improvement in SLR reached statistical significance in the steroid group. However
•this study has been criticised on •statistical grounds because the analysis used only showed change within the active group not a difference between the groups, Re-analysis using X2 tests indicated that the study lacked sufficient power to demonstrate such a difference because . the numbers were too small.
. ..
When the same re-analysis is applied to the data. of Breivik et al (60) the difference in outcome
between treated and untreated groups is not significant. Only if the cross-over patients are included does the difference in outcome achieve statistical significance but this step can be seriously questioned.
In an obscure and rarely quoted article because of its language Czarski (158) demonstrated statistically significant and clinically significant differences in outcome comparing the use of caudal epidural injections of novocaine and hydrocortisone and novocaine alone in the treatment of patients with prolapsed lumbar intervertebral disc (Table .9). Unfortunately, however, the duration of follow-up was not specified• in this study and it is not clear how enduring either the benefit or the difference was. •
Table 9
Treatment of prolapsed intervertebral disc with caudal epidural injections of 1OmL
novocaine 1 per cent (nov) and 25 mg hydrocortisone (HC) or 10 mL novocaine alone
Treatment Number Relief
------------------------------------------------------------ -------------
Complete Significant Marginal None or worse
--------------------------------------------------------------------------
Nov+HC
. Nov
123 22 64 14
60 0 8 35
23
17 .
---------------------------------------------------------------------------------- ------------------ ------------
Source: Based on Czarski (158)
The balance of the published evidence supports the therapeutic use of caudal epidural steroids but does not vindicate it. There are no contrary or hostile . publications, but several enthusiastic, supportive publications. Open trials claim good results in the treatment of sciatic pain, and the results of controlled trials approach but do not achieve convincing, statistical significance. •
'•\ '
The remaining studies involve the lumbar route whose perceived advantage is that the
injection can be targeted more closely to the assumed site of pathology and a lower volume is
•required. The disadvantage is the greater risk of dural puncture.
The literature on lumbar epidural steroids is largely supportive of their use, although more negative studies have been published than in the case of caudal epidural steroids. One aspect of uniformity has been that virtually all trials, both open and controlled, have evaluated the use of lumbar epidural steroids in patients with symptoms of sciatica or nerve root pain. Only Jurmand (88) included an additional large group of patients with simply low back pain . White
26
et al (102) studied patients with a variety of carefully defined diagnoses but did not specify how . many patients with each diagnosis were treated,
. Uncontrolled trials that do not specify the period of follow-up record good results in between
18. er cent and 90per cent of patients.(12,69,75,85,88,89,158)
Most of the studies on lumbar ESI have used methyprednisQlone.
Table 10
Preparations reported for lumbar epidural injections of steroids
Author Saline Local anaesthetica Steroidb Total
(mL) ------------------------
.Drug o;o mL ---- ---------------
Drug mg volume
(mL)
------------------------------------------------------------------------------------------------------------------
Zappala (159) HC 100 3
Yamazaka (164) HC 25
Barry & Kendall (83) 20 MP 80 22
Harley (85) MP 80 2
Burn & Langdon (80) lig 0.75 40 MP 80 43
+HC 25
Swerdlow & Sayle,
Creer(86) 3 MP 80 5
Ito (12) PN 20 ?
Winnie et al. (ISO) MP 80 2
Warr et al (79) lig 40 MP 80 43
+HC 25
Jurmand (88) ns 4
Dike et al (82) 10 MP 80 12
Hartman et al (75) MP 80 2
D'Hoogue et al (69) 10 MP 80 12
Snoek et al (81) MP ' 80 2
•Brown (72) lig 1 3 MP
Bullard & cpc 1 1 DX 8 6
. Houghton (160) +MP 200
Heyse-Moore (70) lig 1 20 MP 80 22
White et al (102) bup 0.25 5 MP 60 7
Green et al (74) 6 MP 808
Jackson et al. (76) 10 MP 120 3
Berman et al (89) bup,.._ 0.5 10 MP 100 13'
Cuckler et al (73) pro 1 5 MP 80 7
Hickey (78) 7 MP 120 10
Anderson & Mosdal (71) lig 1 18 MP 80 20
Rid ey et al. (87) 10 MP 80 12.
Rosen (77) MP 80 2
a proc: procaine; lig: lignocaine; cpc: chlorprocaine; bup: bupivacaine;
b HC: hydrocortisone; MP: methylprednisolone; PN: prednisolone; DX: dexamethasone;
ns: not specified.
•
27
On reviewing the controlled trials from Koes' review (153) (see Table 8) Snoek's trial received the highest methodological score. This trial is however flawed because patients were assessed only twenty four hours after injection which is an inappropriately short period in which to
••" evaluate the anti-inflammatory effect of a long acting steroid preparation. Furthermore only 2
mls of the active treatment were administered which may not have reached the target disc level.
Cuckler's trial (73) which also showed no treatment effect can be criticised on similar grounds. Responses were evalu ted at twenty {our hours , and all injection) were made at the L3/4 level rather t!lan the lower two levels where 90% of disc lesions occur. Furthermore patients who had undergone previous laminectomy were included in which epidural scarring could have limited the spread ofthe injected mixture.
Serrao's study (155) compared steroid and saline epidurally plus 3 mls dextrose intrathecally with 10 mls saline epidurally and 3 mg midazolam with dextrose intrathecally. This trial seemed to show a benefit of midazolam intrathecally for chronic mechanical low back pain. No conclusion can be drawn about ESI in this sample of patients who did not represent the common indication for ESI - sciatic root irritation.
Rocco's study (157) also included post-laminectomy patients and was comparing lignocaine and triamcinolone with 8 mg morphine and lignocaine. Once again no conclusions can be drawn about the efficacy of ESI for sciatica.
Two controlled trials have given favourable results for lumbar epidural steroids. Dilke et al. (82) studied 100 patients with unilateral sciatica. Active treatment consisted of a lumbar epidural injection of 80 mg methylprednisolone in 10 ml normal saline; control treatment was an injection of 1ml of normal saline into an interspinous ligament. Significantly more patients receiving the active treatment had their pain 'clearly relieved'. A greater proportion of actively treated patients had no pain at three months, took no analgesics and resumed work at three months (Table 11). Fewer actively treated patients underwent subsequent surgery or other, non"'surgical treatment but these latter differences were not statistically significant.
The Dilke study (82) has been replicated by Ridley et al (87). These investigators studied 35 patients with sciatic pain with numbness or paraesthesiae in the same distribution as the pain or an appropriate neurological deficit. Active treatment consisted of an epidural injection of
10 mL of normal saline to which 80 mg of methylprednisolone had been added. The control
treatment was an injection of 2 mL of normal saline into an interspinous ligament. A second injection of the same agent was repeated at one week if there had been little or no improvement. If placebo had been used initially and lack of improvement persisted for another week, patients were given active treatment.
I
I
I
!j
n
il .....
I !
I
r j
28
Table 11
Outcome measures following lumbar epidural injection of 40 ml 0.75 per cent lignocaine with 80 mg methylprednisolone (treated) or 1 ml of normal saline (control) injected into an interspinous ligament.
OUTCOME MEAS..U. RE
lJ Pain during admission
Treated
[j Control
X2 = 10.48,p<O.Ol
t1\
Clearly relieved .
16
4
Intermediate
5
7
Clearly not .relieved
14
25
r-1
8
Pain at three months Treated Control
X2=13.89,p < 0.01
None
16
8
..
Not severe
24
20
Severe
1
6
Unknown
3
4
ru••
Work at three months
Treated
Control
Resumed
33
21
Not Resumed
3
14
X2 (with Yates' correction)= 8.1, p=0.004
u Fisher's exact test: p = 0.002
---------------------------------------------- --------------------- ---------------------------------------------
Source: Results ofDilke et al. (82) (abridged)
Ninety per cent of the patients treated act.ively showed at least some improvement compared with 19 per cent of patients in the control group. Patients receiving active treatment showed significant improvements in pain at both one and two weeks following treatment. This improvement was maintained up to 12 weeks but deteriorated by 24 weeks to pre-treatment levels. Only 11 of the 17 patients who responded favourably maintained their pain-relief.
Both these studies demonstrate a statistically significant benefit of the lumbar epidural injections to patients with sciatica but the benefit is of limited duration. Significant' effects were evident only at one week and at three months after which the benefit decreased.
\
The only relevant controlled study from Koes' review on lumbar ESI with a negative result was Klenerman's (156). This seems to indicate a similar proportion of patients (approximately
75%) with sciatica of less than six months duration improve whether treated by saline, depomedrone, bupivacaine or needling of the interspinous ligament. This study contained limited numbers in each group and therefore may not have been powerful enough to detect a statistically significant difference (Table 12).
L i
, I
l_j
29
Table 12
Responses to lumber epidural injections.
'
I
I-.
• I
••"'
•Response Treatment
I; I
'
Normal
saline
Depo
Medrone
Bupivacaine
NeedUng
Total
l_ J
Failed
Not failed
5 4 5
11' 15 11
2 16 25%
10 47 75%
Source: Klenerman et al. (156)
Of the studies on lumbar ESI included in Koes' systematic review which faithfully addresses the question only one is negative (156) whereas two are positive in showing the benefit of lumbar ESI albeit in the short term. (82,87).
I 1
I i
' I
I 1
LJ
r l
f---l
L i
. j
' _.J
Of the caudal ESI studies, 4 tudies suggest a positive efficacious effect, (59,60,63,154)Nersus one study showing no benefit (65), These latter studies however have been criticised on methodological and statistical grounds.
Subsequent to these reviews Carette et al (161) published a significant paper in 1997: in a randomized double blind trial they administered up to three epidural injections of methylprednisolone acetate (80 mg in 8 ml of isotonic saline) or isotonic saline (1ml) to 158 patients with sciatica due to a herniated nucleus pulposus. All patients had Oswestry disability scores higher than 20 (on a scale of 1 to 100, with scores of 20 or less indicating minimal disability and higher scores greater disability). At three weeks, the Oswestry score had improved by a mean of 8.0 in the methylprednisolone group and 5.5 in the placebo group (95% confidence interval for the difference, 7.1 to 2.2) Differences in improvements between the groups were not significant, except for improvements in the finger to floor distance (p =
0.006) and reversal of sensory deficits (p = 0.003), which were greater in. the
methylprednisolone group. After six weeks, the only significant difference was the improvement in leg pain which was greater in the methylprednisolone group (p = .0.03). After three months, there were no significant differences betwen the groups. The Oswestry score had improved by a mean of 17.3 in the methylprednisolone group and •15.4 in the
. placebo group (95% confidence interval for the difference, 9.3 to 5.4). At twelve months the
cumulative probability of back surgery was 25.8% in the methylprednisolone group and
24.8% in the placebo group (p = 0.90). They concluded that although epidural injections of methylprednisolone may afford short term improvement in leg pain and sensory deficits in patients with sciatica due to a herniated nucleus pulposus, this treatment offered no significant functional benefit, nor did it reduce the need for surgery.
!
I
30 i
META ANALYSES OF EPIDURAL STEROID INJECTIONS.
In 1995 Watts and •silagy (162) performed a meta analysis (162). The efficacy of epidural cofticosteroids in the management of sciatica was investigated by meta analysis of all randomized controlled trials. Eleven suitable trials of good qualitY were identified involving a total of907 patients. The use of epidural (caudal or lumbar) steroid in the short term (up to 60 days) increased the odds ratio (OR) of pain relief (over 75% improvement) to 2.61 (95% Cl
1.90 - 3.77) when compared with placebo. Despite some variations in trial characteristics
there was little evidence 'Of significant heterogeneity (p = 0.07). When the trials were analysed for near or total relief of pain in'"the short term the OR is 279 (95% Cl 1.92 - 4.06),
=
for heterogeneity (p
0.07). For long term relief of pain (up to twelve months) the OR is 1.87
(95% Cl 1.31 - 2.68). Efficacy is independent of the route of injection; for caudal epidural
steroid the OR is 3.80 (95% Cl 1.36- 10.6) and for the lumbar epidural steroid 2.43 (95% Cl i
1.177 - 3.74). Adverse events included dtiral tap (2.5%), transient headache (2.3%) and '
transient increase in pain (1.9%). There were no reported long term adverse events. In conclusion, they present quantitative evidence from meta analysis of pooled data from randomized trials that epidural administration of corticosteroids is effective in the management of lumbosacral radicular pain. .
Rapps in 1994 performed a meta analysis of six studies from sixteen identified controlled studies. Criteria for analysis were English language, human adults with I.:BP and/or sciatica, randomized controlled trials which were double blinded or had a blinded observer, abstractable data and outcomes assessed at least one week post injection (163).
The test for heterogeneity was not significant at p< 0.05 indicating that data could be pooled.
r Out of the six studies that met inclusion criteria acute radiculopathy was the diagnosis of five of them.
:
The difference between the proportion improved in the steroid group minus the control group
(saline or local anaesthetic) produced an effect size (ES) of 0.137, 95% Cl (0.032, 0.242) see
I ' graph. Data were insufficient to comment on functional changes including: medication use, return to work, resumption of normal activities, complications, or future utilization.
r.
:I
....,w.
- •--•-•------•------------- -------•---- ------------ •--------------- --- --------.... ; .. ., ., ......- .,.........,..._•.,.._..... ..........:....-l,.,...ll,.,.,...".
I!
31
Effect Size of Epidural Injection on Pain Relief
(Treatment- Control)
,. ---------- ---- "--------•---------------------- ------------------- ----- -----•---- -- ---- -------------
Individual
Olinded RCTs
Cumulative
Blinded RCTs
-0.5 ()
o.s
-0. s
() o.s .I
[]
. .._
ES•Q.I37
Cl•(0.032, 0.242)
il
J Conclusions
These results suggest that ESI has a small but statistically significant benetit in relief from low back pain secondary to acute radiculopathy. The results suggest that on average •14% of individuals who would not have otherwise improved would so so with ESI. Future studies following an adequate study design with sutl1cient patient numbers are needed to address functional outcomes and cost effectiveness.
[]
[J
I '
I I
L_
u
. J
SUMMARY
On the basis of three positive (versus pne negative) controlled studies on lumbar BSI, four controlled studies on caudal BSI, and two favourable meta analyses in the presence of a wealth of evidence of relative safety in clinical usage over mariy years the use of epidural steroid injections are vindicated with certain reservations.
Corticosteroids havbeen introdpced into the epid ral space . for almost half a century. Over this period sev.eral preparations, including Kenalog, have been used extensively on an international basis•.
Despite this vast experience, reported complications of this technique are excessively rare. Furthermore, there is no evidence to suggest that the correct administration of epidural corticosteroids results in any significant short or long term complications.
Epidural corticosteroids have been proposed for the. management of a number of spinal syndromes. However, although the literature is conflicting, there is only evidence to support their efficacy in the management of sciatica. •
Based on the previous material that we have reviewed, we would recommend that the statement, suggesting that Kenalog is not to be used in the epidural space, should be removed from the data sheet. We believe that more research is needed to .fully establish the efficacy of epidural corticosteroids in the management of certain spinal syndromes. •
APPENDIX I
Data Sheets:
1. Kenalog TM I tra-Articular/Intra-Muscular 1998
2. Adcortyl TM Intra-Articular/ Intradermal1998
32 •I
I
I
;
I
. ' ....
. 1.
I i
::
3.
4.
•
I: 5.
6.
7.
8.
• ''f
JH
lftj 9.
10.
33
i
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