PARESTHESIAS ASSOCIATED

WITH GABAPENTIN:

A PARADOX?

Maxime Debrosse, MD

Pain Management fellow

UT-MD Anderson Cancer Center

Faculty mentor: Larry Driver, MD

• Patient story

• Paresthesias

• Compensatory vasodilation

• Gabapentin

• Why him

Outline

• 38yo M h/o sacral chordoma

– s/p partial sacrectomy and sacral root ligation

– Discharged home on Tramadol ER, Norco

• Chronic pain clinic

– Gabapentin started 6mo postop for BTP

• 900mg daily

Patient story

• “Buzzing” in arm after “holding phone to my ears

for a long time.”

– Resolved when arm at rest

• GBP reduced to 300mg daily

– Arm buzzing resolved

• How can that be?

Patient story (continued…)

• Sensory fibers: 4 groups

– Group IV: unmyelinated, slowest conduction

• Noci /Mechano-receptors: skin and skeletal muscle

• Neuropathic: unstable firing of Aδ neurons

– GBP classic action

• Post-ischemic

– extracell K+ w/ contraction, perfusion/hypoxia

– Inward K currentdepolarizationbuzzing

Paresthesias

Al Luwimi et al, 2012 Kukkar et al, 2013 Mense, 2010

• Mild exercise: blood flow by >300%

• In mild exercise, NE from post-ganglionic SN

binds β2-AR NOvasodilation

– muscle blood flow

• Functional sympatholysis

– SNA blocked at post-junctional α1 and α2-AR

• Local SNA reduced to pre-junction α2- and β2-AR

Compensatory vasodilation and SNS

Bancroft et al, 1963 Joyner et al, 2014 Roatta et al, 2010

• α2-AR

– Blocks presynaptic NE release

– Multiple subtypes and locations

• Skeletal muscle

• GBP is an α2-AR agonist

– Descending noradrenergic pathways

GBP and SNS

Takasu et al, 2006 Tanabe et al, 2005 Hayashida et al, 2007 Eason et al, 1993 Trendelenburg, 2003

• GBP at high doses binds presynaptic α2-AR

– Mild exercise: less NE / E binding to β2-AR

• Transient ischemiaK+ current Buzzing

– Intense exercise: less β2-AR action, other

pathways

Proposed mechanism

Joyner et al, 2014

Proposed mechanism

• Tramadol daily NE and 5-HT levels

• GBP binds pre-junctional α2AR

– NE withdrawal?

• 5% of patients who abruptly stop Venlafaxine

report “buzz” sensations

• Potential implication

– Might need tighter GBP dose adjustment in

patients on drugs that NE

Why him?

Campagne, 2005

• Dr. Larry Driver

• MD Anderson Pain faculty

• My co-fellows

• TPS

• All of you

Thanks

1) Al Luwimi I, Anmar A, Al Awami M (2012). Pathophysiology of Paresthesia. In Imbelloni LE (Ed.), Paresthesia (pp. 1-17). InTech. Available from:

http://www.intechopen.com/books/paresthesia/pathophysiology

2) Roatta S, Farina D. Sympathetic actions on the skeletal muscle. Exerc Sport Sci Rev. 2010 Jan;38(1):31-5.

3) Dinenno FA, Joyner MJ. Alpha-adrenergic control of skeletal muscle circulation at rest and during exercise in aging humans. Microcirculation. 2006

Jun;13(4):329-41.

4) Joyner MJ, Casey DP. Muscle blood flow, hypoxia, and hypoperfusion. J Appl Physiol (1985). 2014 Apr 1;116(7):852-7.

5) Barcroft H, Greenwood B, Wheelan RF. Blood flow and venous oxygen saturation during sustained contraction of the forearm muscles. J Physiol.

1963 Oct;168:848-56.

6) Kukkar A, Bali A, Singh N, Jaggi AS. Implications and mechanism of action of gabapentin in neuropathic pain. Arch Pharm Res. 2013 Mar;36(3):237-

51

7) Takasu K, Honda M, Ono H, Tanabe M. Spinal alpha(2)-adrenergic and muscarinic receptors and the NO release cascade mediate supraspinally

produced effectiveness of gabapentin at decreasing mechanical hypersensitivity in mice after partial nerve injury. Br J Pharmacol. 2006

May;148(2):233-44.

8) Tanabe M, Takasu K, Kasuya N, Shimizu S, Honda M, Ono H. Role of descending noradrenergic system and spinal alpha2-adrenergic receptors in

the effects of gabapentin on thermal and mechanical nociception after partial nerve injury in the mouse. Br J Pharmacol. 2005 Mar;144(5):703-14.

9) Hayashida K, DeGoes S, Curry R, Eisenach JC. Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity

after surgery. Anesthesiology. 2007 Mar;106(3):557-62.

10) Eason MG, Liggett SB. Human alpha 2-adrenergic receptor subtype distribution: widespread and subtype-selective expression of alpha 2C10, alpha

2C4, and alpha 2C2 mRNA in multiple tissues. Mol Pharmacol. 1993 Jul;44(1):70-5.

11) Trendelenburg AU, Philipp M, Meyer A, Klebroff W, Hein L, Starke K. All three alpha2-adrenoceptor types serve as autoreceptors in postganglionic

sympathetic neurons. Naunyn Schmiedebergs Arch Pharmacol. 2003 Dec;368(6):504-12

12) Casey DP, Curry TB, Wilkins BW, Joyner MJ. Nitric oxide-mediated vasodilation becomes independent of beta-adrenergic receptor activation with

increased intensity of hypoxic exercise. J Appl Physiol (1985). 2011 Mar;110(3):687-94

13) Gilsbach R, Albarran-Juarez J, Hein L (2011). Pre- versus Postsynaptic signaling by α2-Adrenoceptors. In Current Topics in Membranes. Volume 67,

pp 139-160

14) Zugck C, Lossnitzer D, Backs J, Kristen A, Kinscherf R, Haass M. Increased cardiac norepinephrine release in spontaneously hypertensive rats: role

of presynaptic alpha-2A adrenoceptors. J Hypertens. 2003 Jul;21(7):1363-9.

15) Campagne D. Venlafaxine and Serious Withdrawal Symptoms: Warning to Drivers. MedGenMed. 2005; 7(3): 22.

16) Mense S (2010). Functional Anatomy of Muscle: Muscle, Nociceptors and Afferent Fibers. In Mense S, Gerwin RD (Eds.), Muscle Pain:

Understanding the Mechanisms (pp. 17-48). Springer-Verlag Berlin Heidelberg

References