1. Gabapentinoids in Chronic Low Back Pain
Ashley Daniel MD, PGY1
University of Kansas School of Medicine- Wichita Family Medicine Residency at Ascension Via Christi
June 8th, 2019

2. Ashley Daniel, MD
Ashley Daniel is a family medicine resident at Via Christi. She completed her medical school and undergraduate education at the University of Missouri-Columbia. She plans to practice full-scope family medicine internationally after graduation. Her special interests include obstetrics and the integration of medical and behavioral health.

3. Learning Objectives
Describe current evidence regarding the use of gabapentinoids for chronic low pain.
Discuss the benefits and adverse effects related to the use of gabapentinoids for chronic low back pain.
Discuss future areas of research regarding the use of gabapentinoids for chronic low back pain.
Gabapentinoids: Class of drugs that are derivatives of inhibitory neurotransmitters gamma-aminobutyric acid blocking voltage dependent calcium channels.

4. Current evidence: What we know…
Chronic Low Back Pain: 51-80% lifetime prevalence
We know the MOA of analgesia and anti- epileptic activity is UNKNOWN
Gabapentinoids have demonstrated benefit in neuropathic conditions , but their use is on the rise for non-specific CLBP

5. Current evidence: What we know…
FDA approval for:
Post-herpetic neuralgia
Refractory partial seizures
RCTs showing benefit off-label: 
Diabetic neuropathy
Prophylaxis of frequent migraine headaches
Fibromyalgia

6. Current evidence: What we know…
Multitude of off-label/open label uses
 A common theme in the medical literature for gabapentin is the prevalence of open-label studies
A lack of randomized controlled clinical trials for all but a small number of indications

7. Current evidence: What we know…
Multitude of off-label/open label uses
Bipolar disorder,
Peripheral neuropathy,
Complex regional pain syndrome,
Attention deficit disorder,
Restless legs syndrome,
Trigeminal neuralgia,
Periodic limb movement disorder of sleep,
Alcohol withdrawal syndrome

8. Current evidence: What we know…
Use has tripled over (JAMA Internal Med)
Likely secondary to opioid epidemic
Especially in regards to non-specific low back pain
Older adults on narcotics

9. POEM | Patient Oriented Evidence That Matters
Gabapentinoids for Chronic Low Back Pain: Limited Evidence, More Harm Than Benefit. Am Fam Physician. 2017 Dec 15;96(12):online.
Primary source: Shanthanna H, Gilron I, Rajarathinam M, et al. Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials. PLoS Med ;14(8):e
Gabapentin/Neurontin& Pregabalin/Lyrica

10. Meta-Analysis
Clinical Question: Are gabapentinoids safe and effective in treating patients with chronic low back pain?
Metanalysis, RCTs from Cochran Review, MEDLINE & EMBASE Databases
Databases searched from inception to 2016
Gabapentin/Neurontin& Pregabalin/Lyrica

11. Meta-Analysis
Searched RCTs reporting use of gabapentinoids for LBP > 3 months in adult patients
Pain relief and safety profile were the primary outcomes
8 total studies found; 3 comparison groups
Gabapentin vs placebo
Pregabalin vs “Other analgesics”
Pregabalin as an adjunct to other analgesics
Gabapentin/Neurontin& Pregabalin/Lyrica

12. Heterogenous Results 2 Studies using pregabalin as an adjuvant (n=423)
Largest of them showed no benefit of adding pregabalin to tapentadol
~Tramadol (mu-opioid agonist/NERI)
Data not pooled due to heterogeneity of results
Methodological quality issues
selection bias
Inadequate concealment of randomization
Tapentadol = similar to tramadol
 dual mode of action as an agonist at the mu-opioid receptor and as a norepinephrine reuptake inhibitor

13. Benefits: Limited Evidence
3 studies, 332 patients:
pregabalin vs “other analgesics”
Greater improvement in the other analgesic group
 tramadol, amitriptyline, celecoxib
3 studies, 185 patients:
Gabapentin vs placebo
Minimal improvement in pain

14. Benefits: Limited Evidence
Gabapentinoids have tripled in use (JAMA Internal Med)
No functional outcomes reported
Consider how we assess efficacy of opioids [PEG scale]
What number best describes your pain on average?
How pain has interfered with your enjoyment of life?
How pain has interfered with your general activity?

15. Adverse Effects Adverse Effects:
 Inconsistent reporting of treatment harms
Adverse Effects:
Dizziness - NNH=7; 95% CI 4-30
Fatigue - NNH=8; 95% CI 4-44
Altered mentation - NNH=6; 95% CI 4-15
Vision disturbance - NNH=6; 95% CI 4-13

16. Adverse Effects
 GRADE [Grading of Recommendations Assessment, Development, and Evaluation] : evidence quality low or moderate
Functional outcomes and emotional improvements not reported or showed no significant improvements
Cost???

17. Future Areas of Research:
Large high quality trials to more definitively inform this issue- POEM
Interaction with prescription narcotics?
Many already on prescription pain medications
Does it increase the risk of addiction, respiratory depression and death?
Older adults on gabapentinoids
Interactions with anti-depressants or mood stabilizers

18. Bottom Line:
There is evidence for its use in post-herpetic neuralgia, refractory partial seizures, off- label: diabetic neuropathy and prophylaxis of frequent migraine headaches
Limited number of studies; Limited quality
Inconsistent reporting of treatment harms
Pain reduction low-moderate
2A: systematic review (with homogeneity) of cohort studies
Minus: fails to provide a conclusive answer due to single result with wide confidence interval vs systematic review with some heterogeneity => inconclusive evidence equivalent to Grade D evidence by USPSTF*** NOT RECOMMENDED.

19. Bottom Line: High rate of adverse effects
Few studies have assessed function, those that do found no improvement
Considered Level 2A-
Centre for Evidence-Based Medicine at Oxford
Systematic review with homogeneity of cohort studies
Fails to provide a conclusive answer due to systematic review with some heterogeneity
Equivalent to Grade D Evidence [USPSTF]  NOT RECOMMENDED
2A: systematic review (with homogeneity) of cohort studies
Minus: fails to provide a conclusive answer due to single result with wide confidence interval vs systematic review with some heterogeneity => inconclusive evidence equivalent to Grade D evidence by USPSTF*** NOT RECOMMENDED.

20. Social Determinants of Health
AAFP  the conditions under which people are born, grow, live, work, and age
Economic inequality is increasing in most countries and is associated with a variety of negative outcomes
Indicators of socioeconomic status often used interchangeably
Economic inequality is increasing in most countries and is associated with a variety of negative outcomes

21. Social Determinants of Health
Fliesser M, De Witt Huberts J, Wippert P. The choice that matters: The relative influence of socioeconomic status indicators on chronic back pain- A longitudinal study. BMC Health Serv Res. 2017; 17: 800.
Longitudinal study: education, job position, income, multidimensional index
Back Pain & Disability; surveyed pre & post therapy
Economic inequality is increasing in most countries and is associated with a variety of negative outcomes

22. Social Determinants of Health
Linear regression for predictive strength of each determinant of SES
Intensity best predicted by multidimensional index > job position > education.
Income had no effect
Disability most strongly predicted by education > job position.
Multidimensional index and income had no effect
Interventions should therefore focus on this group of people
Economic inequality is increasing in most countries and is associated with a variety of negative outcomes

23. References
Gabapentinoids for Chronic Low Back Pain: Limited Evidence, More Harm Than Benefit. Am Fam Physician. 2017 Dec 15;96(12):online.
Shanthanna H, Gilron I, Rajarathinam M, et al. Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2017;14(8):e
Goodman CW and Brett AS. A clinical overview of off-label use of gabapentinoid drugs. JAMA Intern Med 2019 Mar 25; [e-pub].
Fliesser M, De Witt Huberts J, Wippert P. The choice that matters: The relative influence of socioeconomic status indicators on chronic back pain- A longitudinal study. BMC Health Serv Res. 2017; 17: 800.

24. Questions?

25. Thank you.