paresthesias associated with gabapentin: a …
TRANSCRIPT
PARESTHESIAS ASSOCIATED
WITH GABAPENTIN:
A PARADOX?
Maxime Debrosse, MD
Pain Management fellow
UT-MD Anderson Cancer Center
Faculty mentor: Larry Driver, MD
• 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
• 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
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