Systematic Reviews of Common Chronic pain Medications and Interventions Trang Nguyen MD, PhD MASI 09.24.15 1.

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Systematic Reviews of Common Chronic pain

Medications and InterventionsTrang Nguyen MD, PhD

MASI 09.24.15

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Long acting opioids: Pain & Function2. Systemic review of 16 randomized controlled trials and 8

observational studies studying efficacy and safety of long-acting opioids in CNCP

n=2617

Studies examined the use of long-acting opioids (taken ≤ twice a day) in CNCP patients –transdermal fentanyl and long acting oral oxycodone, morphine, codeine, and dihydrocodeine

Efficacy regarding reducing pain and improve function

Adverse Effects

Subgroup analysis- which long acting opioid is more effective

Chou R, et al. J Pain and Symptom Management.2003; 26:1026-1048

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Long acting opioids: Pain & Function

Conclusions:

Comparing 1 long acting opioid to another long acting opioid (2 trials)

Insufficient evidence from head to head comparison studies.

Comparing long acting opioids to other types of drugs or placebo (14 trials- mostly placebo, one trial with Darvocet, one trial with Cogentin)

There is insufficient evidence to suggest that long-acting opioid is superior to another in terms of efficacy.

Pain scales varied between trials.

Comparing long acting opioids to short acting opioids in improving pain and function (7 trials)

There is insufficient evidence

Chou R, et al. J Pain and Symptom Management.2003; 26:1026-1048; Review Article

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Efficacy: Oral Opioids1. Meta-analysis of 11 randomized, placebo controlled trials

comparing oral opioids to placebo n=1025

Length 4 days-8 weeks

388/1025 (38%) had open label f/u beyond 8 weeks Only 170 (44%) were on opioids after therapy for 7-24 months

Kalso E, et al. Pain. 2004: 372-380. Systematic Review

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Function: Oral Opioids

Function

5/11 studies reported no significant difference in either self reported overall activity or ADL

1/11 reported improved in disability (Maier, 2002)

2/11 reported lower disability scores during treatment (Watson 1998 and 2003)

Kalso E, et al. Pain. 2004: 372-380. Systemic Review

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Efficacy: Oral Opioids Mean decrease in pain intensity in most studies was

at least 30% with the use of opioids compare to placebo

Effectiveness was comparable in neuropathic and nociceptive pain

However… Tolerance: occurred in 6% patients at one year. Most

patients required increased doses of opioids

Lower doses (Morphine 30 mg and Oxycodone 20 mg PO qd) were not effective

Side effects prevented from increasing dose

Only 3/11 trials used a validated quality of life questionnaire (SF-36 or Sickness Impact Profile) Only 1/11 reported a + difference in quality of life with opioids

We don’t know if opioids improved quality of life

Kalso E, et al. Pain. 2004: 372-380. Systemic Review

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Opioids -Efficacy

Furlan A. Opioids for chronic noncancer pain: a meta-analysis of

effectiveness and side effects. CMAJ. May 23,2006. 174(11) p. 1589-94.

Meta-analysis

Methods:

Literature search up to May 2005

Results

Total- 6019 patients with CNCP

80% nociceptive pain, 12% neuropathic & others

Ages – 40-71 years; average 58 years

63% female and 85% white

Duration of therapy 1 week to 16 weeks

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Results

90% of the studies funded or had > 1 author affiliated with pharmaceutical industry.

17/41 RCTs have adequate randomization 30/39 trials have adequate “double-

blinded” Drop out rate 33% - 38% (cases & controls-

side effects or inadequate pain relief) Not all RCTs have adequate data for meta-

analysis

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Efficacy- Pain relief

Opioids vs. PLACEBO

28 RCTs data available for meta-analysis

Results in favor of opioids

SMD -0.60, 95% CI -0.69 to -0.50

Standard mean difference

SMD = Mean (case) – Mean (controls)

pooled standard deviation

Conclusion persist with subgroup analysis of different opioids and methodological quality

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Efficacy- functional outcomes

Opioids vs. PLACEBO 20 RCTs Results favor opioids

SMD -0.31, 95% CI -0.41 to -0.22

Subgroup analysis Long acting morphine compared to

placebo was not statistically significant Mixed pain subjects also do not have

statistically significant functional relief with opioids

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Opioids vs. other ANALGESICS 8 RCTs Pain relief NOT statistically significant SMD – 0.05, 95% CI -0.32 to 0.21 Subgroup analysis did not change

conclusions NSAIDs, TCAs or methodological quality

Strong opioids (oxycodone and morphine) compared to NSAIDs or TCAs Subgroup analysis was significant for pain relief SMD- 0.34, 95% CI -0.67 to -0.01)

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Efficacy- functional outcomes

Opioids vs. other analgesics

Other analgesics more effective

SMD 0.16, 95% CI 0.03 to 0.30

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Efficacy

Martell B. “Systematic Review: Opioid Treatment for Chronic Back Pain: Prevalence, Efficacy, and Association with Addiction” Ann Intern Med. 2007; 146: 116-27.

Meta-analysis Methods

Literature search up to March 2005

Chronic low back pain (> 3 months)

Oral, topical or transdermal opioids

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Efficacy

Results 18 studies

15 studies for final analysis- 3 excluded quality score poor

1008 patients

8/15 studies used randomized, double blind trial

4/15 studies had placebo controlled

11/15 trials sponsored by pharmaceutical companies

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Results

Opioids vs. Nonopioids or Placebo

4 RCTs- quality score “excellent”

Study duration- mean 64 days (7-16 weeks)

Patient retention- 67%-99%

Average morphine dose- 73mg/day (30-232mg/day)

(most trials do not have pretrial analgesia)

Nonsignificant pooled data

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Conclusions:

Meta-analysis (opioids vs. nonopioids or placebo) no significant effect

SMD- -0.199; 95% CI -0.49 to 0.11; P= 0.136

Sensitivity analysis- (study quality, sample size, study duration, and opioid dose) did not change SMD

Not more effective compared to other analgesics (NSAIDs or TCA)

Opioids have limited efficacy in treatment of CLBP

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Conclusions

Efficacy

Comparing one opioids to another opioids- no significant effect

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Opioids

Opioids in the Management of Chronic

Non-Cancer Pain: An Update of American

Society of the Interventional Pain Physicians’ (ASIPP) Guidelines

Pain Physician 2008: Opioids Special Issue: 11:S5-S62.

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Summary of Evidence- Opioid Effectiveness

Based on the review of multiple systematic reviews

and the available literature, the evidence for

the effectiveness of long-term opioids (specifically

transdermal Fentanyl and sustain release morphine) in reducing pain and improving the functional status for 6 months or longer is available but weak.

Noble M. J. Pain Symptom Manage 2008; 35:214-228. Systematic Review.

Trescot AM. Pain Physician 2008; 11: S181-S200.

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Opioid Effectiveness

For Oxycodone, the level of evidence is limited.

For Hydrocodone and Methadone, the level of evidence is non-existent (opinions- no published evidence regarding effectiveness with long term therapy)

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Hydrocodone

There were no studies evaluating the effectiveness of hydrocodone even though this is the most commonly used drug.

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RecommendationsOpioids

Based on the review of multiple systematic reviews

and the available literature, there is insufficient data for long term opioids with regards to efficacy and improve function.

Patients withdrew from clinical trials secondary to side effects (32% for oral therapy, 17% for transdermal) and insufficient pain relief (12% oral therapy and 5% transdermal)

Substantial heterogeneity among oral studies

Many trials have removal of patients who do not respond leading to high drop out rate. Validity of the trials is questionable.

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Opioid Therapy

G u i d e l i n e f o r t he Use of Chronic Opioid Therapy in Chronic Noncancer Pain-Evidence Review

The American Pain Society in Conjunction with the American Academy of Pain Medicine February 2009

Recommended Reading***

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Comparing Long Acting Opioids

There is insufficient evidence from eight head-to-head trials (three higher-quality) and three observational studies to conclude that any long-acting opioid (sustained-release formulation or transdermal fentanyl) is more beneficial or less harmful than others.

Level of evidence: moderate

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Comparing sustained-release andimmediate-release formulations of opioids

Seven trials (two higher-quality) found no clear differences in benefits or harms between sustained- and immediate-release opioids (level of evidence: high).

Chou, 2003 systematic review.

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Comparisons between different Tramadols

Six trials (three higher-quality) found no clear differences in benefits or harms between extended-release (once/day), sustained-release (twice/day), and immediate release Tramadol (level of evidence: high).

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Comparisons between Tramadol versus opioids

Three trials (one higher-quality) found no clear difference in efficacy between tramadol and different opioids. (level of evidence: moderate). Evidence of differences in harms was inconclusive.

Jensen, 1994- OA- f/u 2 weeks, n= 264

*Mullican, 2001- OA or LBP- f/u 22 days, n= 462

Wilder-Smith, 2001- OA- f/u 1month, n= 57

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Anticonvulsants

Cochrane Review- 2009, Issue 4

RCTs only

Trigeminal neuralgia, post herpetic, diabetic neuropathy, central pain post stroke, IBS, TMJ dysfunction

Mostly oral medication

Carbamazepine

Clonazepam

Gabapentin

Phenytoin

Sodium Valproate

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Anticonvulsants

Results:

23 trials of 6 anticonvulsants

Acute pain- one trail – placebo vs. sodium valproate- no evidence of effectiveness

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Anticonvulsants

Chronic Pain- anti-convulsant is not first line medication

(except for trigeminal neuralgia).

Trigeminal Neuralgia

3 trials of carbamazepine- NNT for effectiveness of 2.5

Post Herpetic Neuralgia

1 trial of Gabapentin – NNT 3.2

Diabetic Neuropathy (1 trial each)

Carbamazepine- NNT 2.3

Gabapentin – NNT 3.8

Phenytoin – NNT 2.1

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Antidepressants

Meta-analyses of randomized controlled trials indicate that tricyclic antidepressants provide effective pain relief for a variety of chronic pain etiologies for assessment periods ranging from 2 to 8 weeks (Category A1

evidence).

In addition, meta-analyses of randomized controlled trials indicate that selective serotonin–norepinephrine reuptake inhibitors provide effective pain relief for a variety of chronic pain etiologies for assessment periods ranging from 3 to 6 months (Category A1 evidence).

A meta-analysis of randomized placebo-controlled trials is equivocal

regarding the efficacy of selective serotonin reuptake inhibitors

in providing effective pain relief for diabetic neuropathy

(Category C1 evidence).

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Benzodiazepines:

One case report indicates that benzodiazepines can provide pain relief for up to 2 months for neuralgic pain syndrome.

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Skeletal muscle relaxants

The literature is insufficient to evaluate

the efficacy of skeletal muscle relaxants in providing pain relief for patients with chronic pain.

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NSAIDs

Randomized controlled trials indicate that NSAIDs compared with placebo provide effective pain relief

for patients with back pain for assessment periods ranging from 2 to 12 weeks.

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Topical agents

Randomized, placebo-controlled controlled

trials of topical agents (e.g., capsaicin, lidocaine, and ketamine) are equivocal regarding relief of peripheral pain for patients with neuropathic pain (e.g., diabetic neuropathy and postherpetic neuralgia).

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Opioids for Chronic Non-Cancer Pain

Washington State Department of Labor and Industries. Guidelines for outpatient prescription of oral opioids for injured workers with chronic, noncancer pain.

Olympia (WA): Washington State Department of Labor and Industries; 2002 Aug.

21 p. [28 references]

Interagency Guideline on Opioid Dosing for Chronic Non-cancer Pain: 2010 Update

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What is New in this Revised Guideline

New data, including scientific evidence to support the 120mg MED dosing threshold

Tools for calculating dosages of opioids during treatment and when tapering

Validated screening tools for assessing substance abuse, mental health, and addiction

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Recommended Principles for prescribing chronic opioids

Single prescriber

Single pharmacy

Patient and prescriber sign opioid agreement

Lowest possible effective dose should be used

Be cautious when using opioids with conditions that may potentiate opioid adverse effects (including COPD, CHF, sleep apnea, current or past alcohol or substance abuse, elderly, or history of renal or hepatic dysfunction).

Do not combine opioids with sedative-hypnotics, benzodiazepines or barbiturates for chronic non-cancer pain unless there is a specific medical and/or psychiatric indication for the combination and increased monitoring is initiated

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Recommended Principles for prescribing chronic opioids

Routinely assess function and pain status

Monitor for medication misuse Random urine drug testing to

objectively assure compliance

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Injection Therapy

Updated Cochrane Review. Staal JB, de Bie RA. Spine. Vol. 34, No.1, pp 49-59. 2009

Injection therapy for subacute and CLBP

18 RCTs (ESI, facet injections, trigger points)

No statistical pooling secondary to heterogeneity of the trials

Conclusion: “There is insufficient evidence to support the use of injection therapy in subacute and CLBP”.

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Injection Therapy

Injection therapy for subacute and CLBP- An

Updated Cochrane Review. Staal JB, de Bie RA. Spine. Vol. 34, No.1, pp 49-59. 2009

ESI vs. Placebo Injections

2 trials evaluate short term effects

One high quality and one low quality study

No significant result for pain relief or other outcomes

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Injection Therapy

Facet Injections vs. Placebo Injections

2 trials (1 high quality and 1 low quality)

Moderate evidence that facet joint injections are not significantly different from placebo injections for short-term pain relief and improvement of disability

Limited evidence that facet joint injections are not significantly different from placebo injections on work attendance.

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Spinal Injection Procedures

Spinal Injection Procedures: A Review of Concepts, Controversies, and Complications. Heran MK, Smith AD. Radiol Clin N. Am 46(2008) 487-514.

Long term efficacy of ESIs has not been shown with lack of a preferred method for administration of medications. The number and frequency of ESIs is arbitrary. Patients should not receive more than 3 injections in total.

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Intra-articular facet blocks and medial branch blocks are equivalent when assessing a patient for facet denervation procedures. However, the false positive rates for both procedures are too high for them to be useful.

Rhizotomy procedures for facet-mediated pain do not provide sufficient long term relief to justify their use. The methods for evaluating which patients will benefit form these procedures are flawed, with no uniformity in how these procedures are performed.

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Complications

Spinal injection procedures can be associated with potentially devastating complications and should not be performed because there are limited data to support their efficacy as diagnostic and therapeutic procedures.

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Potential complications from facet denervation procedures

Infection Bleeding Painful cutaneous dysesthesia Pain caused by neurogenic inflammation Pneumothorax Damage to spinal nerve or motor branches

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Interventional Therapies, Surgery, and Interdisciplinary Rehabilitation for LBP

Interventional Therapies, Surgery, and Interdisciplinary Rehabilitation for LBP: An Evidence Based Clinical Practice Guideline from the American Pain Society. SPINE. V. 34, No. 10, pp 1066-1077. 2009

Surgery for Low Back Pain: A Review for the Evidence for an American Pain Society Clinical Practice Guideline. Chou R, Baisden J, Carragee EJ. SPINE V. 34, No. 10, pp 1094-1109. 2009

Recommended

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Prolotherapy

Condition: NS LBP Level of Evidence: Good: consistent results

from well designed, well conducted studies; at least 2 higher quality trials.

Net Benefit: No benefit

Grade: Panel recommends against the intervention.

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Intradiscal steroid injection

Condition: Presumed discogenic pain Level of Evidence: Good: consistent results

from well designed, well conducted studies; at least 2 higher quality trials.



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Facet injection

Condition: Presumed facet pain Level of Evidence: Fair: at least 1 higher

quality trial, >2 higher quality trials with some inconsistency, or >2 lower quality trials with consistent results, or multiple consistent cohort studies.



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Botulinum toxin injection

Condition: NS LBP Level of Evidence: poor- large and unexplained

inconsistency between higher quality trials;

Net Benefit: Unable to estimate

Grade: Evidence that the intervention is effective is lacking, of poor quality, or conflicting and the balance of benefits and harms cannot be determined.

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ESI

Condition: NS LBP Level of Evidence: poor- large and

unexplained inconsistency between higher quality trials;



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Medial Branch Block (therapeutic)

Condition: Presumed Facet joint pain Level of Evidence: poor- large and unexplained




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Radiofrequency denervation

Condition: Presumed facet joint pain Level of Evidence: poor- large and




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Radiofrequency denervation

Condition: Presumed discogenic pain Level of Evidence: poor- large and unexplained




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Percutaneous Intradiscal Radiofrequency thermocoagulation

Condition: Presumed Facet joint pain Level of Evidence: poor- large and unexplained




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Coblation Nucleoplasty

Condition: Presumed discogenic pain Level of Evidence: NO trials



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Spinal cord Stimulation

Condition: NS LBP Level of Evidence: NO trials;



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Intrathecal therapy

Condition: NS LBP Level of Evidence: NO trials;



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RF Denervation

Condition: Radiculopathy Level of Evidence: poor- large and




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Coblation Nucleoplasty

Condition: Radiculopathy with prolapsed lumbar disc

Level of Evidence: NO trials;



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Spinal cord Stimulation


Level of Evidence: NO trials;



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ESI Condition: Radiculopathy with prolapsed lumbar disc

Level of Evidence: Fair: at least 1 higher quality trial, >2 higher quality trials with some inconsistency, or >2 lower quality trials with consistent results, or multiple consistent cohort studies.

Net Benefit: MODERATE for SHORT TERM only ( 3 months) Mean 10-20 point improvement of VAS pain scale Mean 10-20 point improvement of ODI scale, 2-5 points on

RDQ, or equivalent

Grade: Panel recommends the intervention. +at least fair evidence that intervention improves health outcomes, benefits moderately outweigh harms OR

Benefits are small but there are no significant harms, costs or burden associated with the intervention.

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SCS

Condition: FBSS with persistent radiculopathy


Net Benefit: MODERATE Mean 10-20 point improvement of VAS pain scale Mean 10-20 point improvement of ODI scale, 2-5 points on

RDQ, or equivalent

Grade: Panel recommends the intervention. +at least fair evidence that intervention improves health outcomes, benefits moderately outweigh harms OR

Benefits are small but there are no significant harms, costs or burden associated with the intervention.

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Intradiscal steroid injection



Net Benefit: NO effect vs. chemonucleolysis (NO TRIALS VS. PLACEBO)

Grade: Benefits only slightly outweigh harms, or the balance of benefits and harms are too close to justify a general recommendations

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Lumbar Fusion Outcomes Among Ohio Workers’ Compensation Subjects

Trang Nguyen M.D., Ph.D.

David C. Randolph M.D, Ph.D. M.P.H.

James Talmage MD

Paul Succop PhD

Russell Travis MD

Spine - 2011 Feb 15;36(4):320-31

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Failed Fusion

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Lumbar Fusion Volumes by Diagnoses

Lumbar Fusion by Age & Diagnoses

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Overview of study design

Historical Cohort 725 lumbar fusion cases, 725 computer randomized non-surgical

controls

The primary outcome was return to work status. The secondary outcomes were permanent disability status,

complications, re-operations, and opiate utilization.

Ohio Workers’ Compensation Database

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3,138Injured Workers with Lumbar

Fusionwith Injury dates 01/01/99 -

12/31/2001

2,413 Excluded:

1,001 had lumbar fusion after the cut off date of 7/31/03 and 1,412 have injuries to other body parts in addition to the lumbar spine

725 Final Surgical Subjects

78 ALIF One Level34 ALIF Multi-Level

30 AP 360 One Level39 AP 360 Multi-Level

310 PLIF One Level 68 PLIF Multi-Level

26 Post Uninstr. One Level 5 Post Uninstr. Multi Level

47 Post w/ Instr. One Level 88 Post w/ Instr. Multi Level

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Results: Return to Work, Rehabilitation and Disabled Status

RTW no RTW

Cases 188(25.93%) 367(50.62%)

Controls 483(66.62%) 163(22.48%)

Rehab

Cases 64(8.83%)

Controls 43(5.93%)

PTD

Cases 82 (11.31%)

Controls 11 (1.52%)

7 cases and 14 controls with no RTW status

Loss to follow up = 1.45%

Results: Duration of Time Off

Cases Controls

Total number of days off:

1140+ 735 316+463

Number of days from DOI to DOS:597 + 330

Number of days off work from DOI to DOS:337 + 277 73

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Results: Re-operations

194 cases have re-operations (26.76%)

Re-operations no.(%)

Once 158/194 (81.44%)

Twice 28/194 (14.43%)

> Three 08/194 (4.12%)

No re-operation 531/725 (73.24%)

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Results: Complications

Category no.(%)

264 cases (36.4%)

Early major systemic 45(6.21%) Implant complications 34(4.69%) Late spinal complications 183(25.24%) Neurologic complications 18(2.48%) Wound complications 27(3.72%)

No complications 461(63.59%)

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Results: Mortality

Post op (no.-%) <6 weeks 0/725 (0%) <3months 1/725 (0%) >3 months 16/725(2.2%)

Controls Mortality 11(1.52%)

P value: .26

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Results: Daily amount of Morphine Average daily MEQ (Mean + SD)

Cases Controls P Value 48.06 + 43.88 65.57 + 70.66 <.001

Number of subjects taking opioids

614 (84.69%) 354 (48.83%) <.001

Average daily MEQ before surgery 44.23 + 33.57

Average daily MEQ after surgery 62.31 + 70.80

Maximum daily MEQ 585.00 (controls)

Before surgery 276.00

After surgery 878.00

Patient Characteristic All subjects Adjusted OR

(95% CI) P Value

CasesAdjusted OR

(95%CI) P Value

Controls Adjusted OR

(95%CI) P Value

Current smoker 0.65(0.42-1.01)

.05

Total days off a 0.93(0.92-0.94)

<.001 0.85(0.82-0.88)

<.001

Weekly Wages b 1.09(1.01-1.18)

.02 1.12(1.03-1.21)

.008 1.16(1.02-1.32) .02

Complications c .007

No complications (Reference)

Early Major Systemic 0.25(0.07-0.90)

.03

Implant 0.13(0.02-1.08)

.06

Late Spinal 0.50(0.29-0.87)

.01

Neurologic 0.65(0.12-3.45)

.61

Wound Complications 2.72(0.69-10.66)

.15

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Multivariate Logistic Regression

Patient Characteristic All subjects Adjusted OR

(95% CI) P Value

CasesAdjusted OR

(95%CI) P Value

Controls Adjusted OR

(95%CI) P Value

Days off work prior to surgery d

0.94(0.92-0.97)

<.001

Legal representation 3.43(1.58-7.41)

.002

Morphine(daily) e 0.83(0.71-0.98)

.03

Re-operation 0.42(0.26-0.69)

<.001

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Multivariate Logistic Regression

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Total Days off as Predictor of RTW status

Daily Morphine Equivalents as Predictor of RTW status

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Daily Morphine Equivalents as Predictor of RTW status

Cases’ OR of RTW at 100 MEQ units 0.25, p<.001

Controls’ OR of RTW at 100 MEQ units 0.93, p<.65

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The End..

Thank you for your time!

Systematic Reviews of Common Chronic pain Medications and Interventions Trang Nguyen MD, PhD MASI 09.24.15 1.

Documents

long acting opioid

short acting opioids

j pain

reducing pain

pain functionconclusions

pain intensity

pain scales

use of opioids