Epidural steroid injections medications and dosages

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OREGON HEALTH AND SCIENCE UNIVERSITY OFFICE OF CLINICAL INTEGRATION AND EVIDENCE-BASED PRACTICE

Evidence-Based Practice Summary Epidural Steroid Injections Medications and Dosages

Prepared for: Ashley Valentine, MD Authors: Marcy Hager, MA

DATE: October 2017

BACKGROUND

The underlying mechanism of action of epidurally administered steroid and local anesthetic injections is not well understood (Conn 2009). It is believed that the achieved neural blockade alters or interrupts nociceptive input, reflex mechanism of the afferent fibers, selfsustaining activity of the neurons, and the pattern of central neuronal activities (Boswell 2007; Manchikanti 2002). Few research studies have been conducted to determine the optimal dose and schedule for dexamethasone with epidural steroid injections. Additionally, there has been little research done to determine the type, dose and/or duration of local anesthetics to use with epidural steroid injections to improve clinical outcomes. This evidence brief was conducted to synthesize the literature available on the optimal dose and schedule for dexamethasone and the type, dose, duration of local anesthetics for use with epidural steroid injections.

ASK THE QUESTION

Question 1: In patients receiving epidural steroid injections, what is the minimum-effective dose of dexamethasone to relieve pain?

Question 2: In patients receiving epidural steroid injections, what local anesthetic (type, dose, duration) is associated with improved clinical outcomes and/or harms (ie weakness, cardiotoxicity, osteonecrosis, other)?

SEARCH FOR EVIDENCE

Databases included Ovid MEDLINE, MEDLINEinprocess, the Cochrane Central Register of Controlled Trials (CCRCT) & Cochrane Database of Systematic Reviews (CDSR).

1. exp Injections, Epidural/ (3431)

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2. exp Analgesia, Epidural/ (7707) 3. (epidur* adj3 (inject* or infus* or administ* or analges* or (pain* adj3 relie*))).mp. [mp=title, abstract, original title, name of

substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (15176) 4. 1 or 2 or 3 (15788) 5. exp Steroids/ (832041) 6. 1 and 5 (773) 7. Dose-Response Relationship, Drug/ (391723) 8. (epidur* adj5 (steroid* or dexametha*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (1170) 9. 7 and 8 (19) 10. exp Pain/ (364190) 11. exp pain management/ (27559) 12. exp pain measurement/ (77393) 13. 10 or 11 or 12 (400215) 14. 8 and 13 (751) 15. 6 or 9 or 14 (1162) 16. limit 15 to english language (1084) 17. limit 16 to (meta analysis or systematic reviews) (100) 18. limit 16 to (controlled clinical trial or guideline or randomized controlled trial) (197) 19. limit 16 to (comparative study or evaluation studies or validation studies) (130) 20. exp Epidemiologic Studies/ (2177321) 21. 16 and 20 (342) 22. 17 or 18 or 19 or 21 (549) 23. 16 not 22 (535)

Filters/limits included articles published in English in the last 15 years.

CRITICALLY ANALYZE THE EVIDENCE

Questions 1: In patients receiving epidural steroid injections, what is the minimum-effective dose of dexamethasone to relieve pain?

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The literature search resulted in a number of studies including dexamethasone, although few studies were found analyzing the different doses between treatment groups and/or the most effective dose for relieving pain. One systematic review and two randomized-controlled studies (RCT) were found researching the most effective dose to relieve pain. One systematic review (De Oliveira 2011) was conducted to evaluate the dose-dependent analgesic effect of perioperative dexamethasone. In the meta-analysis that included 24 RCTs with approximately 2,500 patients, dexamethasone >0.1mg/kg was found to reduce postoperative pain and opioid consumption. One RCT (Ahadian 2011) investigated the efficacy, dose-response profile, and safety of three doses of epidural dexamethasone. Subjects were randomized to receive transforaminal epidural dexamethasone 4mg, 8mg, or 12mg. The primary outcome for this measure was a reduction in radicular pain according to the visual analog scale from baseline. The study found there was no statistical difference between groups for either measure (all P values <0.05). The last RCT (Hong 2017) included investigated the effects and optimal dose of epidural dexamethasone on pain after major abdominal surgery. Patients were randomized to receive one of three treatment regimens: Dexamethasone 5mg (1mL) with normal saline (1mL) (Group D) or dexamethasone 10 mg (2mL) (Group E) or 2mL of normal saline (Group C) mixed with 8mL of 0.375% ropivacaine as a loading dose. The resting and effort visual analogue scale (VAS) was significantly lower in Group E compared to Group C at every time point through the study period. Only the resting VAS in Group D was lower at 2 hours and 6 hours after surgery.

In conclusion, there is moderate quality evidence for the use of dexamethasone to relieve pain. The studies demonstrated that dexamethasone was effective at reducing pain, but is it unclear the minimum-effective dosage to achieve the best outcomes. Overall, studies did not demonstrate a statistically significant reduction in pain between treatment groups receiving different doses.

Question 2: In patients receiving epidural steroid injections, what local anesthetic (type, dose, duration) is associated with improved clinical outcomes and/or harms (ie weakness, cardiotoxicity, osteonecrosis, other)?

There was limited literature found evaluating what local anesthetic (type, dose, duration) with epidural steroid injections is associated with improved clinical outcomes and/or harms. The majority of the research compared the effects of epidural steroid injections with or without local anesthetics. This brief includes studies that reported the type, dose or duration of local anesthetics used in treatment and includes ten studies: five systematic reviews, one RCT and four non-randomized studies.

One systematic review (Conn 2009) evaluated the effect of caudal epidural injections with or without steroids in managing various types of chronic low back and lower extremity pain. Eighteen RCTs and twenty observational studies were included in the systematic review using a variety of doses and durations of local anesthetics. One of the randomized trials evaluated spinal stenosis with or without steroids with local anesthetic (lidocaine 0.5%) showed positive results for short- and long-term relief. The included observational studies also showed positive short-term and long-term improvement. Another systematic review (Diwan 2012) evaluated the effect of cervical interlaminar epidural injections in managing various types of chronic neck and upper extremity pain. For cervical disc herniation, the review authors rated the evidence as "good" for cervical epidural with local anesthetics and steroids, whereas the rated with local anesthetic only as "fair". For axial or

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discogenic pain, the review authors rated evidence as "fair" for local anesthetic, with or without steroids. For spinal stenosis, the review authors rated the evidence as "fair" for local anesthetic, with or without steroids. And for postsurgery syndrome, the review authors rated the evidence as "fair" for local anesthetic, with or without steroids.

The systematic review conducted by Manchikanti assessed the efficacy of three categories of epidural injections for lumbar and spinal stenosis performed with saline with steroids, local anesthetic alone, or steroids with local anesthetic. The review found that adding bupivacaine to steroids showed very short-term (three-six weeks) effectiveness in three trials with 173 patients, whereas two trials with 142 patients reported a lack of effectiveness. There were seven trials assessing lidocaine as a sole agent or lidocaine with steroids and 3 trials assessing bupivacaine alone in comparison to bupivacaine with steroid. All three of the bupivacaine trials showed positive results with similar results with bupivacaine combined with steroid to avoid surgical interventions. Based on a qualitative synthesis of evidence of seven active-controlled trials comparing lidocaine to lidocaine with steroid, effectiveness was equal in both groups except in disc herniation where potential superiority was demonstrated. Six studies with 649 patients were utilized for pain improvement ratings, comparing lidocaine to lidocaine with steroid. They showed no difference in pain improvement between both groups at three or 12 months. Functional status was also assessed with inclusion of six studies at three months and seven studies at 12 months showing no difference in functional improvement between lidocaine alone or lidocaine with steroid at three or 12 months. This analysis showed the effectiveness of lidocaine and lidocaine with steroid for pain relief and functional status at three months and also 12 months with results slightly favoring local anesthetic alone.

Another systematic review (Liu 2015) investigated the effectiveness and safety of epidural steroid injections in patients with lumbar spinal stenosis (LSS). The epidural local anesthetic injection group in the analysis reported no significant difference for most common measures. The final systematic review (Meng 2015) included presented a current, comprehensive picture of epidural injections of anesthetic with steroids compared to those using local anesthetic alone. Thirteen RCTs involving 1,465 patients were include in the meta-analysis; Group I included patients administered with epidural injections of anesthetic with steroids and Group 2 included patients administered with local anesthetic alone. The overall number of injections per year was 3.2+/-1.3 and 3.4+/-1.2 with average total relief per year of 29.3+/-19.7 and 33.8+/-19.3 weeks in groups 1 and 2, respectively, and the opioid intakes decreased from baseline by 12.4 and 7.8 mg, respectively. However, there were no significant differences between the two groups in terms of the outcomes except in the total relief time.

A prospective observational study (Cohen 2013) determined whether a standard, clinical local anesthetic injection can predict outcomes for epidural steroid injections (ESI). Patients received two injections of 1 mL of 1% lidocaine two weeks apart. A small but significant relationship was found between standardized subcutaneous pain score and reduction in leg (r = -0.21, 95% CI -0.38 to -0.04; P = 0.03) and back pain (r = -.022, 95% CI -0.36 to -.07; P = 0.03). One retrospective study (Delport 2004) determined patient satisfaction, relief of pain, frequency of injections, change of function, and subsequent surgical rate in patients who received ESIs. The intervention included transforaminal or caudal fluoroscopically guided ESIs with 60 to 100mg of triamcinalone in combination with local anesthetic or normal saline. Patients who received two or more injections had better results (P = .006). Number of injections and amount of relief initially after injection was significant (P = .007).

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One retrospective observational study (El- Yahchouchi 2014) assessed whether the immediate anesthetic response of pain relief (sensory blockade) or weakness (motor blockade) after lumbar transforaminal epidural steroid injection (TFESI) is associated with longer term effectiveness in pain relief and functional recovery. Patients were give 20 mg lidocaine (1 mL of 2% lidocaine). If there was no neurological change after one - two minutes, corticosteroid was injected betamethasone sodium phosphate/betamethasone acetate 12 mg in 2 mL; triamcinolone acetonide 80 mg in 2 mL; or preservative-free dexamethasone sodium phosphate 10 mg in 1 mL. The immediate pain response following TFESI was only weakly associated with successful response in pain or functional improvement at two-month follow-up (Spearman correlations, P = 0.20, 0.21, respectively). The pain score at two weeks was much more strongly associated with two-month response in both pain (P = 0.59) and function (P = 0.51). One RCT (Ghahreman 2010) was found comparing the outcomes of transforaminal injection of steroid and local anesthetic, local anesthetic alone, or normal saline, and intramuscular injection of steroid or normal saline. Patients were randomized to receive transforaminal injection of steroid and local anesthetic, local anesthetic alone, or normal saline, and intramuscular injection of steroid or normal saline. A significantly greater proportion of patients treated with transforaminal injection of steroid (54%) achieved relief of pain than did patients treated with transforaminal injection of local anesthetic (7%) or transforaminal injection of saline (19%), intramuscular steroids (21%), or intramuscular saline (13%). A cohort study (Wewalka 2012) was conducted to evaluate the efficacy of serial CT-guided transforaminal nerve root infiltrations with a supplement of tramadol for patients with persistent, radicular pain. 65 infiltrations were carried out with pain relief in more than 90% of the patients within 24 hours and an average pain reduction of 64%. Six months post-injection, 23 of 34 patients were available for follow-up (67.6%), and had a successful pain reduction of 84% on average.

Overall, there is low quality of evidence for type, dose, or duration of local anesthetic with epidural steroid injections for improved outcomes. The studies included used a variety of doses and durations of local anesthetic, therefore we cannot conclude what type, dose, or duration is associated with improved clinical outcomes and/or harms.

Question 1 Primary Literature:

PICO Question: In patients receiving epidural steroid injections, what is the minimum-effective dose of dexamethasone to relieve pain?

Outcome: Reduce Pain

Author/Da Purpose

Study Design &

Sample

Outcomes

Design Limitations

te

of Study

Methods

Total # of Studies: 3 # of Systematic Reviews: 1 # of RCTs: 2

De Oliveira,

To perform a Systematic review with meta-

G.S.J., et al.,

meta-analysis analysis of RCTs

2011,

to evaluate

Anesthesiology the dose-

dependent

analgesic

effect of

24 RCTs with 2,751 subjects were included

In a meta-analysis of approximately 2,500 patients, dexamethasone, > 0.1 mg/kg, reduced postoperative pain and opioid consumption.

Study Limitations = None

Systematic Review Review did not address

focused clinical question Search was not detailed or

exhaustive Quality of the studies was

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Lower Quality Rating if:

Studies inconsistent (wide variation of treatment effect across studies, populations, interventions, or outcomes varied)

Studies are indirect

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Ahadian, F.M., et al., 2011, Regional Anesthesia & Pain Medicine

perioperative dexamethaso ne

To investigate the efficacy, doseresponse profile, and safety of three doses of epidural dexamethaso ne

RCT; Subjects were randomized to receive transforaminal epidural dexamethasone 4 mg, 8mg, or 12mg. The primary outcome measure for this study was reduction in radicular pain according to the visual analog scale from baseline, with 30% reduction or higher considered clinically meaningful. Secondary measures included the Oswestry Low Back Disability Scale, and adverse events. Outcomes were assessed at 1, 4, 8, and 12 weeks after injection.

98 subjects; 4 mg (n = 33), 8 mg (n = 33), or 12 mg (n = 32)

Mean radicular pain according to the visual analog scale compared with baseline was reduced 41.7%, 33.5% and 26.6% AT 4, 8, and 12 weeks, respectively, after injection. Oswestry disability ratings declined from "moderate" at baseline to "minimal" at 4, 8, and 12 weeks after injection. There was no statistical difference between groups for either measure (all P values < 0.05, Bonferronicorrected). Parallel effects were observed in "impression of change" and "satisfaction" measures. No serious adverse events were noted.

DATE: October 2017

not appraised or studies were (PICO question is

of low quality Methods and/or results

were inconsistent across studies Study Limitations =

None RCTS

quite different from the available evidence in regard to population, intervention, comparison, or

Lack of blinding

outcome)

Lack of allocation

concealment Stopped early for benefit Incorrect analysis of ITT Selective reporting of

measures (e.g., no effect outcome)

Studies are imprecise (When studies include few patients and few events and thus have

Large losses to F/U

wide confidence

Difference in important

intervals and the

prognostic factors at baseline results are uncertain)

Publication Bias (e.g. pharmaceutical company sponsors study on effectiveness of drug, only small, positive studies found)

Hong, J.M., et al., 2017, Pain Physician

To investigate the effects and optimal dose of epidural dexamethaso ne on pain after major abdominal surgery

RCT; Patients were assigned to receive one of three treatment regimens: Dexamethasone 5 mg (1 mL) with normal saline (1 mL) (Group D) or dexamethasone 10 mg (2 mL) (Group E) or 2 mL of normal saline (Group C) mixed with 8 mL of 0.375% ropivacaine as a loading dose.

120 ASA physical status I and II men, scheduled for gastrectomy, were enrolled; 40 in each group

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The resting and effort VAS was significantly lower in Group E compared to Group C at every time point through the study period. On the contrary, only the resting VAS in Group D was lower at 2 hours and 6 hours after surgery. Total fentanyl consumption of Group E was significantly lower compared to other groups. There was no difference in adverse effect such as hypotension, bradycardia,

Study Limitations = None

RCTS Lack of blinding Lack of allocation

concealment Stopped early for benefit Incorrect analysis of ITT Selective reporting of

measures (e.g., no effect outcome)

Large losses to F/U Difference in important

Increase Quality Rating if:

Large Effect Dose-response gradient Plausible confounders or other biases increase certainty of effect

Quality (certainty) of evidence for studies as a whole:

High Moderate Low Very Low

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