Gabapentinoids in Routine Anesthesia Practice

Educational Objectives

The goal of this program is to improve pain management. After hearing and assimilating this program, the clinician will be better able to:

1. Differentiate nociception from pain.
2. Elaborate on the mechanism of action of gabapentinoids for mitigation of pain sensations.
3. Cite current literature addressing efficacy of gabapentinoids and adverse events associated with their use in a multimodal perioperative pain strategy.

Summary

Challenge for perioperative physician: addressing pain often not as simple as “fifth vital sign;” nociception much different from pain; use of large quantities of opioids not likely to lead to good outcomes; advantages and disadvantages to multimodal approach to pain

Nociception vs pain: nociceptive signal different from pain; pain involves human experience; includes unpleasant sensory and emotional experiences associated with pain and potential for tissue damage; nociception describes signal; stimulus in periphery travels through dorsal root ganglion and into dorsal horn; eventually produces afferent signal involving calcium channels; dorsal horn can promote afferent signaling to cortex of brain (increased nociceptive signal with potential for interpretation at level of brain); gabapentinoids can play role at this point

Mechanism of action of gabapentinoids: α2δ subunit focuses on calcium conductance; decrease in calcium conductance results in decreased release of neurotransmitters in synaptic cleft, leading to decrease in nociceptive signals to brain; further actions occur in dorsal horn; after injury, calcium channels begin to increase in number, leading to antegrade flow of calcium channels from dorsal root into dorsal horn with increase in pain signal to brain; increased calcium conductance leads to increased signal; analgesic actions of gabapentinoids target dorsal horn; descending efferent modulation of pain occurs at level of dorsal horn; gabapentinoids can increase efferent signal to further modulate pain signal; gabapentinoids also work at higher centers in cortex; gabapentinoids reduce afferent signal, affect efferent signal modulation, potentially affect cortex, and have potential anti-inflammatory effects; gabapentinoids activate astrocyte-dependent descending noradrenergic inhibition originating from locus coeruleus; potentially inhibit descending serotonergic facilitation; inhibit inflammatory mediators in animal models; can influence affective component of pain (seen on positron emission tomography); does not work through γ-aminobutyric acid

Role of histone deacetylase (HDAC) inhibitors: can possibly prescribe valproate to rescue gabapentin efficacy in patients who fail to respond; proposed mechanism of action to upregulate glutamate transporter-1 receptor in astrocytes to facilitate noradrenergic inhibition

Advantages of gabapentinoids: reported in literature to lower pain scores at 24 hr, decrease opioid consumption at 24 hr, and improve postoperative nausea, vomiting, pruritis, anxiety, and satisfaction; 10 to 20% reduction in opioid or oral morphine equivalent; 10% reduction in Numeric Rating Scale pain scores; number needed to treat 11 to show benefit for postoperative nausea and vomiting

Disadvantages of gabapentinoids: include dizziness and sedation

Variations by time point: studies and meta-analyses using time point of 2 hr postoperatively usually favor prescription of gabapentinoids; results statistically significant; possibly clinically significant; at 24 hr, data still favor gabapentinoids, but less so

Respiratory depression: Myhre et al (2016) administered combinations of remifentanil, pregabalin, and placebo to 12 volunteers; remifentanil plus pregabalin associated with additive reduction of pain to cold pressor test; respiratory depression potentiated by adding pregabalin to remifentanil; Weingarten et al (2015) found gabapentinoids associated with 50% increased risk for respiratory events

Prevention of chronic postsurgical pain: Clarke et al (2012) performed systematic review; chronic postsurgical pain defined as pain at ≥2 mo postoperatively; concluded data supportive of perioperative gabapentin and pregabalin for reducing incidence of chronic pain; Cochrane review by Chaparro et al (2013) concluded available evidence does not support efficacy of gabapentin and pregabalin for prevention of chronic postsurgical pain; review by Richebe et al (2018) concluded significant heterogeneity and biases in reported trials; some older meta-analyses did not include some data with bad outcomes; data currently insufficient to form firm conclusion

Implementation of gabapentinoids in clinical practice: American Society of Anesthesiologists (2012) — recommended implementation of multimodal pain-management therapy whenever possible; Schmidt et al (2013) — recommended doses of 300 mg pregabalin or 1200 mg gabapentin preoperatively and pregabalin 150 mg twice a day or gabapentin 600 mg 3 times per day postoperatively; can be considered large doses for gabapentinoid-naive patients; adjustment of dose for patients with renal problems critical; concluded gabapentinoids effective; failure to administer preoperative dose should not preclude intraoperative administration via nasogastric tube (rarely used)

Prescriptions for gabapentinoids: clinical trend over past 15 yr toward multimodal analgesia; prescriptions for gabapentinoids have tripled; clinical overview of off-label use of gabapentinoids by Goodman et al (2019) concluded clinicians who prescribe gabapentinoids for off-label treatment of pain should be aware of limited evidence and should acknowledge to patients potential benefits uncertain for most off-label uses; pharmaceutical companies have paid penalties and settlements for improper marketing of medications for off-label uses; adverse effects include dizziness, somnolence, and gait disturbances with dose-dependent effects; number needed to harm from 3 to 11; compelling published evidence for some gabapentinoid prescriptions lacking; caution must be exercised

Concomitant use of opioids and gabapentinoids: retrospective review of opioid-related deaths by Gomes et al (2017) found significant dose-dependent odds risk for opioid-related death for patients who received gabapentinoids in addition to opioids ≤120 days prior to death

Use of gabapentinoids in clinical practice: Aubrun et al (2019) — concluded gabapentinoids should not be used systematically; gabapentinoids decrease postoperative pain at 2 hr and 24 hr and decrease consumption of morphine by 10 to 20%, but risk of sedation, dizziness, and visual impairment significant; risk-benefit ratio did not justify use in routine practice; however, improving titration may allow potential advantages of gabapeninoids to be exploited; risk-benefit analysis should be individualized; consider for patients who should not receive opioids; patients already taking gabapentinoids should continue perioperatively; consider slower preoperative titration to avoid some adverse side effects

Potential uses: consider for pronociceptive surgeries (eg, total joints, spine, amputations); consider if sedation desired

Dosing strategies: optimal dosing strategy currently not known

Risk-benefit analysis: risk for respiratory depression with concomitant use of opioids; additional risks include sedation, dizziness, and visual impairment; number needed to harm similar to number needed to treat for postoperative nausea and vomiting; risk for polypharmacy; problems may arise when patients (particularly elderly patients) given multiple medications; benefits include decreased pain at 2 and 24 hr and decreased opioid consumption

Speaker’s recommendations: gradual preoperative acclimation vs rapid perioperative administration; administer gabapentin 300 mg for 1 wk with optional second and third week; start with 100 mg for patients aged >65 yr; optimal postoperative time course unknown; do not immediately discontinue postoperatively; gabapentinoids should be among last postoperative medications to discontinue; statistical significance does not necessarily equate to clinical significance; anesthesia professionals do not have opportunity to begin titration of gabapentinoids several weeks before surgery; collaboration with surgeons necessary

Readings

American Society of Anesthesiologists Task Force on Acute Pain Management: Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2012 Feb;116(2):248-73; Aubrun F et al: Revision of expert panel’s guidelines on postoperative pain management. Anaesth Crit Care Pain Med 2019 Aug;38(4):405-11; Chaparro LE et al: Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst Rev 2013 Jul 24(7):CD008307; Chincholkar M: Analgesic mechanisms of gabapentinoids and effects in experimental pain models: a narrative review. Br J Anaesth 2018 Jun;120(6):1315-34; Clarke H et al: The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesth Analg 2012 Aug;115(2):428-42; Gomes T et al: Gabapentin, opioids, and the risk of opioid-related death: a population-based nested case-control study. PLoS Med 2017 Oct;14(10):e1002396; Goodman CW et al: A clinical overview of off-label use of gabapentinoid drugs. JAMA Intern Med 2019 May 1;179(5):695-701; Hayashida KI et al: Strategies to treat chronic pain and strengthen impaired descending noradrenergic inhibitory system. Int J Mol Sci 2019 Feb 14;20(4); Kharasch ED et al: Wherefore gabapentinoids?: was there rush too soon to judgment? Anesthesiology 2016 Jan;124(1):10-2; Myhre M et al: Pregabalin has analgesic, ventilatory, and cognitive effects in combination with remifentanil. Anesthesiology 2016 Jan;124(1):141-9; Richebe P et al: Persistent postsurgical pain: pathophysiology and preventative pharmacologic considerations. Anesthesiology 2018 Sep;129(3):590-607; Schmidt PC et al: Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology 2013 Nov;119(5):1215-21; Weingarten TN et al: Multimodal analgesic protocol and postanesthesia respiratory depression during phase I recovery after total joint arthroplasty. Reg Anesth Pain Med 2015 Jul-Aug;40(4):330-6.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Hustak was recorded at the Texas Society of Anesthesiologists 2019 Annual Meeting, held September 5-8, 2019, in Lost Pines, TX, and presented by the Texas Society of Anesthesiologists. For information about upcoming CME opportunities from the Texas Society of Anesthesiologists, please visit tsa.org. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AN620501

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.