Journal club reviewing recent JAMA surgery and Anesthesia & Analgesia publications on the topic, in addition to background on mechanism of action, pharmocokinetics, and evidence based medicine thus far.

1. The Great Gabapentin Debate
Updates from the Literature
DACCPM Journal Club January 4, 2018
Kellie Jaremko, M.D, Ph.D. (CA-1)

2. Mechanism of Action
Anesthesiology 11 2013, Vol.119, 1215-1221. doi:10.1097/ALN.0b013e3182a9a896

3. Pharmacokinetics & Pharmacodynamics
• Only absorbed in the
duodenum & can be
impaired by antacids (for
up to 2hrs following
ingestion of the latter;
bicitra)
• Minimally protein-bound
• Peak plasma levels 2-3hrs
but peak in CSF may be
delayed
• Renally excreted without
significant metabolism
• Elimination half life 4.8–8.7 h
Drug Design, Development and Therapy 2014:8

4. Existing EBM on Perioperative Gabapentin
In same review 6 studies
(5 with doses >600mg)
showed some indication
of decreased
neuropathic post-op pain
while 4 showed none. All
small studies.
Meta-analysis by Fabritus
et. al found many biased
studies but when
gabapentin as add-on to
another non-opioid
analgesic regimen, avg
reduction in 24-h
morphine consumption of
1.2 mg. Gabapentin
increased adverse events
(RR 1.61)
Ho et. Al. Meta-analysis found “Cumulative 24 h opioid
consumption was also lower (WMD, 7.25 mg). Gabapentin was
associated with an increased risk of sedation (Peto OR 3.86; 95% CI
2.50–5.94) but less opioid-related side effects such as vomiting (Peto
OR 0.58; 95% CI 0.39–0.86)” (Pain 126 (2006) 91–101)

5. Pro:
Con:

6. Study Design
Pre-op 4 pills (1200mg GP
Or 0.5mg lorazepam
+ 3 inactive pills)
Post-op for 72hrs:
2 pills TID (600mg GP
Or 2 inactive pills)
Follow-up for 2 yrs

7. Results
• Extensive Baseline assessments were
similar across populations
• Median time to pain resolution was
84 days (interquartile range [IQR], 36-
203 days) in patients receiving
gabapentin and 73 days (IQR, 36-231
days) in patients receiving active
placebo.
• Participants receiving gabapentin
had a 24% increase in the rate of
opioid cessation after surgery (HR,
1.24; 95%CI, 1.00-1.54; P = .05) as
reported in Table 3. Median time to
opioid cessation was 25 days (IQR, 8-
53 days) in patients receiving
gabapentin and 32 days (IQR, 9-55
days) in patients receiving active
placebo.
• No significant difference in sedation
or dizziness (P = .23) in full protocol of
gabapentin or placebo.
• Patients receiving gabapentin
reported less constipation than those
receiving active placebo (61.5%vs
72.8%; P = .02) as well as more
impaired coordination (42.3%vs
32.7%;P = .03)and rash (13.0%vs6.9%;
P = .04).

8. Limitations
• Single center study
• Exclusion criteria:
• kidney disease, current gabapentin or pregabalin use, cognitive impairment, history of excessive
sedation or adverse reaction to gabapentin, coexisting chronic pain (>4/10 anywhere, excluding
the future surgical site), suicidality assessed by the Beck Depression Inventory-II, pregnancy, ataxia,
dizziness, sedation, narrow-angle glaucoma, severe respiratory insufficiency, history of gastric bypass
surgery, and obstructive sleep apnea requiring CPAP
• “our permissive regimen may have increased between-patient variance as physicians
prescribed different medications to different patients.”
• Morphine equivalent doses intra- and post-op??

9. Study Design
• Retrospective analysis of adult patients that underwent “major” (>90 minute) laproscopic
surgery between Jan 2010 – July 2014 (n= 8,567)
• Binary outcome based on review of documented Phase 1 recovery respiratory depression
events defined as:
1. hypoventilation (3 episodes of <8 respirations/minute)
2. apnea (episode lasting ≥10 seconds)
3. hypoxemia (3 episodes of oxyhemoglobin desaturations [<90%, with or without nasal cannula],
as measured by pulse oximetry)
4. pain-sedation mismatch (defined as a Richmond Agitation Sedation Score16 of −3 to −5 and a
numeric pain score of >5
OR
• Administration of naloxone to treat respiratory depression
• Unplanned use of NIPPV devices (for patients not using these devices preoperatively dx OSA),
• Cases notable for a failure to extubate or that required reintubation
• Propensity matched 2 controls to 1 gabapentin patient based on baseline characteristics

10. Results
In propensity
matched
comparison
gabapentin
increased
likelihood of
respiratory
depression
(OR, 1.26
[95% CI, 1.02–
1.58]; P = .04)

11. Limitations
• Retrospective study design
• Nurse witnessing, identification and recording of events
• Imprecise characterization of chronic pain conditions, substance use
history, medication tolerance (opioids, gabapentinoids – based on MAR at
the time)

12. What do these papers add to the
debate?
• Coordinated pre and post op
gabapentin may decrease the
number of days a patient is on
opioids.
• Reported pain in immediate
post-op period or in 6 – 12
months is not significantly
effected.
• Respiratory depression may be
increased with gabapentin,
especially in combination with
opioids
• Increased vigilance, training,
and screening of post-op staff
may need to be addressed if
pre-op gabapentin is given

13. Unanswered Clinical Questions
• How many days of decreased post-op opioid use are clinically significant?
• How selective does patient selection need to be and does CPC or pre-op
contact need to initiate higher doses of gabapentin earlier to see benefits?
• Does addition of gabapentin help or hinder ERAS with longer PACU times
and sedation risk?
• Would truly opioid sparing intraoperative medication choices decrease
potential adverse effects of gabapentin or unmask its inadequate single
dose effect on acute pain?
• ….?

14. References:
• Schmidt, Peter C., et al. "Perioperative GabapentinoidsChoice of Agent, Dose, Timing,
and Effects on Chronic Postsurgical Pain." Anesthesiology: The Journal of the American
Society of Anesthesiologists 119.5 (2013): 1215-1221.
• Ho, Kok-Yuen, Tong J. Gan, and Ashraf S. Habib. "Gabapentin and postoperative pain–a
systematic review of randomized controlled trials." Pain 126.1 (2006): 91-101.
• Kong, V. K. F., and M. G. Irwin. "Gabapentin: a multimodal perioperative drug?." British
journal of anaesthesia 99.6 (2007): 775-786.
• Fabritius, M. L., et al. "Gabapentin for post‐operative pain management–a systematic
review with meta‐analyses and trial sequential analyses." Acta Anaesthesiologica
Scandinavica 60.9 (2016): 1188-1208.
• Sills, Graeme J. "The mechanisms of action of gabapentin and pregabalin." Current
opinion in pharmacology 6.1 (2006): 108-113.
• Felix, Ricardo, Aida Calderón‐Rivera, and Arturo Andrade. "Regulation of
high‐voltage‐activated Ca2+ channel function, trafficking, and membrane stability by
auxiliary subunits." Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 2.5
(2013): 207-220.
• Tjandrawinata, Raymond R., et al. "Single dose pharmacokinetic equivalence study of
two gabapentin preparations in healthy subjects." Drug design, development and
therapy 8 (2014): 1249-1255.
• Han, C., et al. "The Efficacy of Preoperative Gabapentin in Spinal Surgery: A Meta-
Analysis of Randomized Controlled Trials." Pain physician 20.7 (2017): 649-661.

15. Post-presentation additions
Audience participant directed me to Anesthesiology 2016; 124:141-9 that
showed potentiation of respiratory depression by addition of pregabalin to
remifentanil in healthy volunteers, as well as additive analgesia in
combination.
The editorial by Karasch et. al.
(Anesthesiology 2016; 124:10-2)
provides more insight into this
conundrum.
Do the analgesic benefits outweigh
the risks? What we need is more
data to further assess who, if anyone
will benefit with acceptable risks.