Adverse effects of gabapentin and lack of anti-allodynic efficacy of amitriptyline in the streptozotocin model of painful diabetic neuropathy.
Amitriptyline and gabapentin are the primary treatments for painful diabetic neuropathy (PDN), and it is clear that they produce beneficial effects, but there are questions about these treatments that have not been adequately addressed. For example, although there is a growing consensus that the therapeutic effects of amitriptyline in pain patients are independent of its effects on mood, it is not clear that amitriptyline has specific and direct effects on pain. There is also a fairly broad consensus that gabapentin is safe and well tolerated, but the side-effect profile of gabapentin has not been adequately assessed in pain populations. The rat streptozotocin (STZ) model of PDN was used (a) to assess the effects of amitriptyline on objective, quantitative measures of tactile allodynia, a common type of pain in PDN patients, and (b) to assess the side effects of gabapentin using measures of motor/ambulatory and cognitive function. Amitriptyline did not attenuate STZ-induced mechanical allodynia, even after chronic administration of high doses. Gabapentin produced robust anti-allodynic effects but also produced deficits in tests of motor/ambulatory and cognitive functions. The present experiments suggest that the beneficial effects of amitriptyline in PDN may not be a result of anti-allodynic efficacy and that gabapentin produces robust anti-allodynic effects but may also produce significant motor and cognitive deficits even at or near the lowest effective doses. These findings challenge the consensus opinions about these primary treatments for PDN and suggest that their therapeutic and adverse effects should be explored further in pain patients.
Lindner
Mark D
MD
Department of Neuroscience Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492, USA. mark.lindner@bms.com
Bourin
Clotilde
C
Chen
Ping
P
McElroy
John F
JF
Leet
John E
JE
Hogan
John B
JB
Stock
David A
DA
Machet
Frederic
F
D000588:Amines / Q000009:adverse effects / Q000627:therapeutic use*; D000639:Amitriptyline / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced; D003509:Cyclohexanecarboxylic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D000077206:Gabapentin; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013311:Streptozocin; D005680:gamma-Aminobutyric Acid / Q000009:adverse effects / Q000627:therapeutic use*
D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D000639:Amitriptyline; D005680:gamma-Aminobutyric Acid; D013311:Streptozocin; D000077206:Gabapentin