In order to facilitate ease in finding pertinent studies
for us, I've hyperlinked them for you. Additionally, in order to save bandwidth, I've now
removed those abstracts which have no significance for patients not taking Neurontin for
off-label purposes. These abstracts are to the end of 1998. Follow the links at the bottom
of the page to link to newer research.
Neurology 1999 Jan 15;52(2):321-7 Cognitive effects of
topiramate, gabapentin, and lamotrigine in healthy young adults. Martin R, Kuzniecky R, Ho
S, Hetherington H, Pan J, Sinclair K, Gilliam F, Faught E University of Alabama at
Birmingham Epilepsy Center, Department of Neurology, University of Alabama at Birmingham
35294-0021, USA. OBJECTIVE: To study the acute and steady-state cognitive effects of three
new antiepileptic drugs (AEDs): gabapentin, lamotrigine, and topiramate. BACKGROUND:
Several newer antiepileptic medications approved recently by the Food and Drug
Administration are gaining attention as efficacious alternatives to established AEDs.
Greater tolerability with fewer side effects are reported in some. However, the potential
cognitive effects of these newer AEDs have received limited attention. METHODS: Healthy
young adults randomized to either of the three drugs were administered tests of attention,
psychomotor speed, language, memory, and mood at baseline (predrug), acute single-dose
period, and after 2 and 4 weeks on the drug. RESULTS: Compared with baseline, the
topiramate group had selective, statistically significant declines on measures of
attention and word fluency at acute doses, whereas the other two AED groups had no
performance changes. At the 2- and 4-week test periods, only the topiramate subjects
continued to display neurocognitive effects from drug administration. CONCLUSIONS: Results
demonstrate potential acute and steady-state adverse cognitive effects for topiramate,
whereas minimal effects were displayed for either gabapentin or lamotrigine in young
healthy adults. Publication Types: Clinical trial Randomized controlled trial PMID:
9932951, UI: 99129731 J Clin Psychopharmacol 1998 Dec;18(6):461-4 Gabapentin does not
alter single-dose lithium pharmacokinetics. Frye MA, Kimbrell TA, Dunn RT, Piscitelli S,
Grothe D, Vanderham E, Cora-Locatelli G, Post RM, Ketter TA Biological Psychiatry Branch,
National Institute of Mental Health, Bethesda, Maryland 20892, USA. maf@helix.nih.gov
Lithium (Li) and gabapentin are both exclusively eliminated by renal excretion. When used
in combination, a competitive drug-drug interaction could possibly alter Li renal
excretion with important clinical implications considering the rather narrow therapeutic
index of Li. This study examined the single-dose pharmacokinetic profiles of Li in 13
patients receiving placebo and then steady-state gabapentin (mean daily dose: 3,646.15
mg). During both phases, a single 600-mg dose of Li was orally administered with serial Li
levels obtained at time zero and at 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours.
The pharmacokinetic parameters assessed were the following: area under the concentration
time curve (AUC) for Li, maximal concentration of Li (Li Cmax), and time to reach peak Li
concentration (Li Tmax). For patients receiving gabapentin, the mean Li AUC at 72 hours
was 9.91+/-3.54 mmol x hr/mL and did not differ significantly from the mean Li AUC of
10.19+/-2.89 mmol x hr/mL for patients receiving placebo. The mean Li Cmax was 0.69+/-0.13
mmol/L for gabapentin patients and did not differ from the mean Li Cmax of 0.72+/-0.15
mmol/L for placebo patients. The mean serum Li Tmax was 1.38+/-0.62 hours for gabapentin
patients and did not differ significantly from the mean serum Li Tmax of 1.5+/-0.91 hours
for placebo patients. These data indicate that gabapentin treatment at this high
therapeutic dose does not cause clinically significant alterations in short-term Li
pharmacokinetics in patients with normal renal function. These preliminary data warrant
further controlled study in a larger, more heterogenous patient sample and a longer
duration of assessment, but they do suggest that these two medications may be administered
in combination for the management of bipolar disorder. Publication Types: Clinical trial
Randomized controlled trial PMID: 9864078, UI: 99079782 Presse Med 1998 Dec 12;27(39):2062-9 [Pain therapy]. [Article in
French] Donnadieu S, Djian MC Unite d'evaluation et de traitement de la douleur, Hopital
Laennec, Paris. DND.Laennec@invivo.edu NEW OPIOID ANALGESICS: Progress in pain reliet has
recently been achieved with the introduction of new opioid analgesics such as tramadol and
the pediatric preparation of codeine phosphate as well as powerful long-release opioids
which can be administered per os, or percutaneously for transdermal fentanyl.
CO-ANALGESICS: Other drugs, mainly antidepressants and anti-convulsants, can be usefully
combined with analgesics. New serotonin uptake inhibitors and anticonvulsants (gabapentin
and lamotrigin) have the advantage of better tolerance. None of these drugs has marketing
approval in France for their pain relieving effects. The same is true for clonidine and
neostigmine which, after spinal infusion, potentialize opioids and for ketamine which can
relieve neuropathy pain by dissociative anesthesia. NEW ANTI-MIGRAINE DRUGS: New drugs
have been developed for specific types of pain such as migraine. The new
"triptans" are tolerated better than sumatriptan and is reimbursed by the
national social security. REFRACTORY NEUROPATHY PAIN: Indications for electrical
stimulation techniques conducted in a neurosurgery unit have been identified. Stimulators
may be implanted in spinal or supra-spinal localizations. REGULATORY ASPECTS: New
legislation has reorganized health care for pain relief in France. The new texts take into
consideration personnel training, the health care network and progress in therapeutics.
PMID: 9893699, UI: 99109577 Acta Neurol Scand 1998 Dec;98(6):458-60 A case of myokymia-cramp
syndrome successfully treated with gabapentin. Serrao M, Cardinali P, Rossi P, Parisi L,
Tramutoli R, Pierelli F Istituto di Clinica delle Malattie Nervose e Mentali, Universita
La Sapienza, Roma, Rome, Italy. We report a case of "myokymia-cramp syndrome", a rare and benign disease
consisting of muscular cramps in the upper and lower limbs associated with generalized
myokymias. In our patient, cramps had been present since adolescence and had increased in
frequency and duration during the last 3 years, occurring about 8 or 9 times a day. Cramps
were mainly nocturnal and also precipitated by walking; a previous treatment with
carbamazepine did not improve the symptoms. Gabapentin therapy proved to be very
satisfactory in relieving muscular cramps with a relatively low dosage (600 mg/day) and
without any remarkable side effects. The possible interpretation of the mechanism involved
in gabapentin induced relief of cramps is discussed. Gabapentin should be considered as a
safe alternative treatment for muscular cramps. PMID: 9875627, UI: 99090805 J Neurol Sci 1998 Oct;160 Suppl 1:S57-63 The natural history and the
effects of gabapentin in amyotrophic lateral sclerosis. Mazzini L, Mora G, Balzarini C,
Brigatti M, Pirali I, Comazzi F, Pastore E Fondazione Salvatore Maugeri, Institute of Care
and Research (IRCCS), Medical Centre of Rehabilitation, Veruno (No), Italy. Glutamate excitotoxicity seems to play an important role in the aetiopathogenesis and
progression of Amyotrophic Lateral Sclerosis (ALS). Gabapentin is a modulator of the
glutamatergic system and has been shown to prolong survival in the transgenic model of
familial ALS. It has also been demonstrated to slow the decline of arm strength in human
sporadic cases. The aim of our study was to assess the effects of different dosages and
duration of treatment of gabapentin on the natural history and survival of ALS patients. A
total of 110 patients affected by definite ALS entered the study. After a 6-12 month
period of observation, patients were randomly assigned to receive oral gabapentin 500
mg/day (Group A) or 1000 mg/day (Group B) for 6 months. In addition a group of patients
received gabapentin 500 mg/day for 6 months and 1000 mg/day for a further 6 months (Group
C). A group of 121 patients referred to our Institute, who received only symptomatic
treatment, was considered as the control group (Group D). Each patient was seen at entry
and every 3 months. All average slopes were negative but the comparison of all slopes
showed a trend toward a slower rate of decline of muscle strength loss in all treated
groups of patients compared with the control group. The differences were statistically
significant. Analysis between the pretreatment and treatment period showed a statistically
significant decrease of the decline of muscle strength and Norris score during the
treatment period. Survival analysis showed a significantly longer survival in treated
patients of Groups B and C. Our study suggests that gabapentin may be an effective drug
for ALS; hence a controlled trial involving a sufficient large number of patients is
warranted. PMID: 9851651, UI: 99066976 JAMA 1998 Dec 2;280(21):1837-42 Gabapentin for the treatment of
postherpetic neuralgia: a randomized controlled trial. Rowbotham M, Harden N, Stacey B,
Bernstein P, Magnus-Miller L UCSF Pain Clinical Research Center, University of California,
San Francisco 94115, USA. CONTEXT: Postherpetic neuralgia (PHN) is a syndrome of often
intractable neuropathic pain following herpes zoster (shingles) that eludes effective
treatment in many patients. OBJECTIVE: To determine the efficacy and safety of the
anticonvulsant drug gabapentin in reducing PHN pain. DESIGN: Multicenter, randomized,
double-blind, placebo-controlled, parallel design, 8-week trial conducted from August 1996
through July 1997. SETTING: Sixteen US outpatient clinical centers. PARTICIPANTS: A total
of 229 subjects were randomized. INTERVENTION: A 4-week titration period to a maximum
dosage of 3600 mg/d of gabapentin or matching placebo. Treatment was maintained for
another 4 weeks at the maximum tolerated dose. Concomitant tricyclic antidepressants
and/or narcotics were continued if therapy was stabilized prior to study entry and
remained constant throughout the study. MAIN OUTCOME MEASURES: The primary efficacy
measure was change in the average daily pain score based on an 11-point Likert scale (0,
no pain; 10, worst possible pain) from baseline week to the final week of therapy.
Secondary measures included average daily sleep scores, Short-Form McGill Pain
Questionnaire (SF-MPQ), Subject Global Impression of Change and investigator-rated
Clinical Global Impression of Change, Short Form-36 (SF-36) Quality of Life Questionnaire,
and Profile of Mood States (POMS). Safety measures included the frequency and severity of
adverse events. RESULTS: One hundred thirteen patients received gabapentin, and 89 (78.8%)
completed the study; 116 received placebo, and 95 (81.9%) completed the study. By
intent-to-treat analysis, subjects receiving gabapentin had a statistically significant
reduction in average daily pain score from 6.3 to 4.2 points compared with a change from
6.5 to 6.0 points in subjects randomized to receive placebo (P<.001). Secondary
measures of pain as well as changes in pain and sleep interference showed improvement with
gabapentin (P<.001). Many measures within the SF-36 and POMS also significantly favored
gabapentin (P< or =.01). Somnolence, dizziness, ataxia, peripheral edema, and infection
were all more frequent in the gabapentin group, but withdrawals were comparable in the 2
groups (15 [13.3%] in the gabapentin group vs 11 [9.5%] in the placebo group).
CONCLUSIONS: Gabapentin is effective in the treatment of pain and sleep interference
associated with PHN. Mood and quality of life also improve with gabapentin therapy.
Publication Types: Clinical trial Multicenter study Randomized controlled trial Comments:
Comment in: JAMA 1998 Dec 2;280(21):1863-4 PMID: 9846778, UI: 99061235 JAMA 1998 Dec 2;280(21):1831-6 Gabapentin for the symptomatic
treatment of painful neuropathy in patients with diabetes mellitus: a randomized
controlled trial. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M,
LaMoreaux L, Garofalo E Department of Neurology, University of Wisconsin, Madison 53792,
USA. backonja@neurology.wisc.edu CONTEXT: Pain is the most disturbing symptom of diabetic
peripheral neuropathy. As many as 45% of patients with diabetes mellitus develop
peripheral neuropathies. OBJECTIVE: To evaluate the effect of gabapentin monotherapy on
pain associated with diabetic peripheral neuropathy. DESIGN: Randomized, double-blind,
placebo-controlled, 8-week trial conducted between July 1996 and March 1997. SETTING:
Outpatient clinics at 20 sites. PATIENTS: The 165 patients enrolled had a 1- to 5-year
history of pain attributed to diabetic neuropathy and a minimum 40-mm pain score on the
Short-Form McGill Pain Questionnaire visual analogue scale. INTERVENTION: Gabapentin
(titrated from 900 to 3600 mg/d or maximum tolerated dosage) or placebo. MAIN OUTCOME
MEASURES: The primary efficacy measure was daily pain severity as measured on an 11-point
Likert scale (0, no pain; 10, worst possible pain). Secondary measures included sleep
interference scores, the Short-Form McGill Pain Questionnaire scores, Patient Global
Impression of Change and Clinical Global Impression of Change, the Short Form-36 Quality
of Life Questionnaire scores, and the Profile of Mood States results. RESULTS: Eighty-four
patients received gabapentin and 70 (83%) completed the study; 81 received placebo and 65
(80%) completed the study. By intent-to-treat analysis, gabapentin-treated patients' mean
daily pain score at the study end point (baseline, 6.4; end point, 3.9; n = 82) was
significantly lower (P<.001) compared with the placebo-treated patients' end-point
score (baseline, 6.5; end point, 5.1; n = 80). All secondary outcome measures of pain were
significantly better in the gabapentin group than in the placebo group. Additional
statistically significant differences favoring gabapentin treatment were observed in
measures of quality of life (Short Form-36 Quality of Life Questionnaire and Profile of
Mood States). Adverse events experienced significantly more frequently in the gabapentin
group were dizziness (20 [24%] in the gabapentin group vs 4 [4.9%] in the control group;
P<.001) and somnolence (19 [23%] in the gabapentin group vs 5 [6%] in the control
group; P = .003). Confusion was also more frequent in the gabapentin group (7 [8%] vs 1
[1.2%]; P = .06). CONCLUSION: Gabapentin monotherapy appears to be efficacious for the
treatment of pain and sleep interference associated with diabetic peripheral neuropathy
and exhibits positive effects on mood and quality of life. Publication Types: Clinical
trial Multicenter study Randomized controlled trial Comments: Comment in: JAMA 1998 Dec
2;280(21):1863-4 PMID: 9846777, UI: 99061234 Anesth Analg 1998 Dec;87(6):1360-6 The anti-allodynic effects of
amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain. Abdi S, Lee
DH, Chung JM Department of Anesthesiology and Critical Care, The Massachusetts General
Hospital, Harvard Medical School, Boston 02114, USA. abdi@etherdome.mgh.harvard.edu The
management of patients with neuropathic pain is challenging. There are only a few reports
regarding the acute effects of the commonly used adjuvant drugs amitriptyline (AMI),
gabapentin (GBP), and lidocaine (LDC) on neuropathic pain behaviors in animal models.
Thus, the purpose of this study was to investigate the acute effects of AMI, GBP, and LDC
on behavioral signs of mechanical allodynia and the site of action of these drugs using a
rat model of neuropathic pain. Under general anesthesia with halothane, neuropathic injury
was produced in rats by tightly ligating the left L5 and L6 spinal nerves. In Experiment
1, baseline mechanical allodynia data were recorded, and the animals were randomly divided
into five groups: Group 1 received saline intraperitoneally (IP), Group 2 received AMI
(1.5 mg/kg IP); Group 3 received GBP (50 mg/kg IP), Group 4 received an IV saline infusion
for 10 min, and Group 5 received LDC (10-mg/kg IV infusion) for 10 min. Measurements of
mechanical allodynia were repeated 0.5, 1, 2, and 4 h and 1, 3, and 7 days after
treatment. In Experiment 2, rats were prepared similarly to the first experiment, and a
single unit activity of continuous discharges of injured afferent fibers was recorded from
the left L5 fascicles before and until 1 h after treatment. All animals developed
neuropathic pain behavior within 7 days after surgery. All three tested drugs were
effective in increasing the threshold for mechanical allodynia as early as 30 min after
treatment, and the effect lasted for at least 1 h. Furthermore, AMI and LDC reduced the
rate of continuing discharges of injured afferent fibers, whereas GBP did not influence
these discharges. Our findings clearly demonstrate an attenuation of neuropathic pain
behavior in rats treated with AMI, GBP, or LDC. Finally, the site of action of LDC seems
to be primarily in the periphery, and that of GBP is exclusively central, whereas that of
AMI seems to have both peripheral and central components. IMPLICATIONS: In the present
study, we examined the effectiveness of three drugs commonly used for the treatment of
neuropathic pain. Systemic injections of amitriptyline, gabapentin, or lidocaine produced
pain-relieving effects in this established model for neuropathic pain in rats, which
supports their clinical use in managing patients with neuropathic pain syndromes. PMID:
9842827, UI: 99056961 Pain 1998 Nov;78(2):139-43 A case of spinal cord injury-related
pain with baseline rCBF brain SPECT imaging and beneficial response to gabapentin. Ness
TJ, San Pedro EC, Richards JS, Kezar L, Liu HG, Mountz JM Department of Anesthesiology,
Pain Treatment Center, University of Alabama at Birmingham, 35233-6810, USA.
tim.ness@ccc.uab.edu Central pain following spinal cord injury is poorly understood, and is often resistant
to conventional pain therapy regimens. We describe an individual with paraplegia who for
many years experienced rapidly fluctuating, severe, unilateral pain below the level of his
lesion. Prior to the initiation of pharmacological treatment, regional cerebral blood flow
(rCBF) was measured during PAIN and NON-PAIN states using single photon emission computed
tomography (SPECT). When experiencing pain, the subject had increased anterior cingulate
gyrus blood flow, increased thalamic blood flow bilaterally and increased somatosensory
cortex blood flow contralaterally but decreased caudate blood flow bilaterally. The
subject's subsequent clinical course included a trial of gabapentin which produced a
substantial reduction in frequency and average intensity of his episodic pain and which
has been maintained for almost 2 years. This case demonstrates the correspondence between
rCBF and pain associated with spinal cord injury and also suggests the potential utility
of gabapentin for treatment of this central pain state. PMID: 9839825, UI: 99053560 Semin Neurol 1998;18(3):389-95 Multiple sclerosis: symptomatic
therapies. Metz L Department of Clinical Neurosciences, Faculty of Medicine, University of
Calgary and University of Calgary MS Clinic, Foothills Hospital, Alberta, Canada. Although
new disease-altering treatments offer hope for those with multiple sclerosis, they are not
appropriate for most. Management of symptoms, however, can help everyone with the disease.
Several new therapies, including tizanidine, intrathecal baclofen, botulinum toxin
injections, gabapentin, ondansitron, thalamic stimulation, and lamotrigine, increase our
treatment options. Better understanding of the sleep disorders that commonly occur in
those with multiple sclerosis will help us treat another disabling symptom. This chapter
reviews the medical and surgical management of multiple sclerosis symptoms, including
these new options. Publication Types: Review Review, tutorial PMID: 9817541, UI: 99032479
Eur Neurol 1998 Nov;40(4):191-200 Effects of gabapentin on the different
components of peripheral and central neuropathic pain syndromes: a pilot study. Attal N,
Brasseur L, Parker F, Chauvin M, Bouhassira D Unite d'Evaluation et de Traitement de la
douleur, Boulogne, Service de Neurochirurgie, le Kremlin-Bicetre and INSERM U-161, Paris,
France. Anticonvulsants are widely used in the treatment of neuropathic pain, and are assumed
to act preferentially on lancinating, shooting pain. In the present study, the effects of
gabapentin, a novel anticonvulsant, were evaluated systematically on both spontaneous and
evoked pain in 18 patients with peripheral nerve injuries or central lesions. Gabapentin
was administered orally in gradually increasing doses up to a maximum of 2,400 mg/day.
Evaluations of spontaneous ongoing and paroxysmal pain, allodynia and hyperalgesia were
performed at the beginning of the study ('baseline') and 6 weeks after the steady-state
dose had been reached. Quantitative sensory tests were used to measure detection and pain
thresholds to mechanical and thermal stimuli and the responses to suprathreshold stimuli.
Gabapentin induced a moderate and statistically significant relief of ongoing spontaneous
pain and was particularly effective in reducing paroxysmal pain. A striking finding was
the significant effect on brush-induced and cold allodynia. In contrast, no effects were
observed on detection and pain thresholds to static mechanical and hot stimuli. Side
effects were generally minor and did not interfere with everyday activities. The present
study suggests that gabapentin has preferential antihyperalgesic and/or antiallodynic
effects, and is equally effective in pain due to peripheral nerve injuries and central
lesions. Publication Types: Clinical trial Controlled clinical trial PMID: 9813401, UI:
99032987 Brain Res 1998 Nov 9;810(1-2):93-9 Systemic gabapentin and
S(+)-3-isobutyl-gamma-aminobutyric acid block secondary hyperalgesia. Jones DL, Sorkin LS
Department of Anesthesiology, University of California San Diego, Anesthesia Research
Labs-0818, 9500 Gilman Drive, La Jolla, CA 92093-0818, USA. Gabapentin (GBP) and S(+)-3-isobutyl-gamma-aminobutyric acid (IBG) are anticonvulsant
agents which are effective against many clinical and experimental neuropathic pain states.
We examined the efficacy of these agents in a new rat model of secondary mechanical
hyperalgesia generated by a mild thermal injury. Under brief halothane anesthesia, an
injury was induced by applying one heel to a hot surface (52.5 degreesC) for 45 s. GBP,
IBG or saline was injected i.p. just prior to the injury. Mean mechanical withdrawal
threshold (MWT) was determined using von Frey hairs before and at 30 min intervals for 3 h
following the injury. MWT outside the injury area decreased post-injury (secondary
hyperalgesia, allodynia), but primary (site of injury) mechanical hyperalgesia was not
observed. Secondary hyperalgesia exhibited a tendency toward recovery over time. Time to
onset of the anti-allodynic effect of GBP was 30-60 min. The minimum effective GBP dose
was 100 mg/kg; 300 mg/kg GBP totally inhibited the drop in MWT, but was accompanied by
pronounced sedation. Anti-allodynic effects of IBG were apparent at the first post-injury
measure of MWT (30 min). Thirty milligrams per kilogram was the minimum effective dose;
100 mg/kg IBG totally blocked the allodynia with minimal side effects. Our findings
demonstrate a dose-dependent blockade of the mechanical sensitivity caused by a mild
thermal injury by both GBP and IBG. Results indicate that IBG is more effective than GBP
in this model at doses which do not cause sedation. These observations support the
suggested use of these or related gamma-amino acid analogues as an effective treatment for
post-operative pain. Copyright 1998 Elsevier Science B.V. PMID: 9813259, UI: 99032896 Am J Phys Med Rehabil 1998 Sep-Oct;77(5):451-4 Gabapentin for relief
of spasticity associated with multiple sclerosis. Dunevsky A, Perel AB Department of
Rehabilitation Medicine, Kingsbrook Jewish Medical Center, Brooklyn, New York 11203, USA.
The use of a recently released anticonvulsant, gabapentin, in the treatment of spasticity
in two patients with multiple sclerosis is reported. Gabapentin was chosen because of its
GABA-ergic effect and because previously reported studies have shown that it is well
tolerated compared with other GABA-mimetic medication. Satisfactory release of spasticity
with significant improvement of functional outcome was noted in both cases. Both patients
were first treated with gabapentin for one month at 300 mg per day and then, with no
reported side-effects, at 400 mg per day. Before treatment, spasticity (graded with
modified Ashworth Scale) in one patient was 3 for left lower and 2 for right lower limbs,
and Expanded Disability Status Scale (EDSS) was 7; ambulation was limited to a few steps
with a standard walker. After two weeks of treatment, spasticity was 2 and 1 for the left
and right lower limbs, respectively. At three-month intervals, spasticity was +1 for left
and 1 for right lower limbs, and EDSS was 6; the patient could ambulate 75 to 100 m with a
standard walker. In the second patient, spasticity before treatment was 2 for both lower
and left upper limbs. EDSS was 5.5, and ambulation was confined to 100 m with a cane.
Spasticity improved to +1 in lower and 1 in left upper limbs after two weeks and to 1 and
normal after three months. At three months, EDSS was 3 and the patient could ambulate for
long distances without an assistive device. We suggest that gabapentin can be used
effectively to decrease spasticity without significant side effects in patients with
multiple sclerosis. PMID: 9798839, UI: 99013183 Rev Neurol 1998 Apr;26(152):618-20 [No title available]. [Article
in Spanish] Sanchez-Valiente S Servicio de Neurologia, Hospital de Calatayud, Zaragoza,
Espana. INTRODUCTION: The antiepileptic drug gabapentin has begun to be used successfully in
some cases of neuropathic pain. Its mechanism of action is still unknown, but seems to be
related to a positive effect on the synthesis and liberation of the neurotransmitter GABA.
CLINICAL CASES: Based on the observations of other authors, we used this drug in dosage
varying between 900 and 1,200 mg/day, in three patients with neuropathic pain, of both
central and peripheral origin, and in whom the usual treatments had been unsatisfactory or
could not be tolerated because of side-effects. The patients had been diagnosed as having
trigeminal neuralgia, post-herpetic neuralgia in the area of the first branch of the
trigeminal nerve and a thalamic infarct which gave rise to a contralateral Dejerine-Roussy
syndrome, respectively. In all three cases, administration of gabapentin was followed by
such a striking improvement of the pain that co-adjuvant treatment could be reduced or
stopped, with excellent tolerance and a minimal incidence of side-effects. CONCLUSIONS:
Gabapentin should be borne in mind in the treatment of this type of pain, particulaly when
the usual treatment cannot be given or is insufficient to control pain, especially in
elderly patients in whom there is often reduced tolerance of drugs. PMID: 9796018, UI:
99012110 J Psychiatr Res 1998 Sep-Oct;32(5):261-4 An open label study of
gabapentin in the treatment of acute mania. Erfurth A, Kammerer C, Grunze H, Normann C,
Walden J Dept. of Psychiatry, LMU University Hospital, Munchen, Germany. Recent anecdontal single case reports have suggested that the new antiepileptic drug
gabapentin might be effective in the treatment of manic episodes and in the prophylaxis of
bipolar disorder. In the present open trial, 14 patients with acute mania were treated for
up to 21 days with gabapentin in a dose range from 1200 to 4800 mg/day. Six patients were
treated with gabapentin as add-on medication and 8 patients were treated with a high dose
of gabapentin alone. Gabapentin was both efficacious and safe when applied in combination
with other drugs such as lithium and valproic acid. All patients in the add-on group and
4/8 patients on gabapentin monotherapy finished the 21 day protocol. Analysis of the
scores of the Bech-Rafaelsen Mania Assessment Scale (BRMAS) of these patients showed that
the mean BRMAS score declined from 37.7 to 7.8 on day 21 in the add-on group and from 27.8
to 9.0 in 4/8 patients finishing 21 days in the monotherapy group. It is suggested that
gabapentin monotherapy might be useful in selected patients to treat modest but not severe
manic states. In addition, gabapentin in conjunction with other effective mood stabilisers
seems to be safe and efficacious in the treatment of severe mania. PMID: 9789203, UI:
99005632 Neuropsychobiology 1998 Oct;38(3):198-9 Renal impairment as a
possible side effect of gabapentin. Grunze H, Dittert S, Bungert M, Erfurth A
Psychiatrische Klinik der Universitat,Munchen, Deutschland. A bipolar I manic patient was treated successfully by adding gabapentin to perazine and
clonazepam. Also initially tolerated well, an increase of creatinine after several weeks
of GP (2000 mg) was observed which was reversible after discontinuation of GP. It is
suggested that the possibility of renal dysfunction should be kept in mind with the usage
of gabapentin. PMID: 9778609, UI: 98453524 Neuropsychobiology 1998 Oct;38(3):192-7 Lamotrigine and
gabapentin. Ferrier IN University Department of Psychiatry, University of Newcastle upon
Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, UK. The anticonvulsants carbamazepine and sodium valproate have efficacy in hypomania,
bipolar depression and in the prophylaxis of bipolar disorder. This paper reviews
published evidence on the effects of the new anticonvulsants gabapentin and lamotrigine in
bipolar disorder. The conclusion is that there is good evidence from open studies to
indicate that randomised double-blind trials of these compounds should be carried out. The
pharmacology of these anticonvulsants is reviewed and putative predictors of good response
identified. PMID: 9778608, UI: 98453523 Electroencephalogr Clin Neurophysiol 1998 Aug;109(4):321-30
Pharmacological control of facilitatory I-wave interaction in the human motor cortex. A
paired transcranial magnetic stimulation study. Ziemann U, Tergau F, Wischer S,
Hildebrandt J, Paulus W Department of Clinical Neurophysiology, University of Gottingen,
Germany. ziemann@codon.nih.gov A novel paired transcranial magnetic stimulation (TMS)
paradigm with a suprathreshold first and a subthreshold second stimulus was used in
healthy volunteers to investigate the acute effects of a single oral dose of various
CNS-active drugs on short-interval motor evoked potential (MEP) facilitation. MEPs were
recorded from the relaxed abductor digiti muscle. Three peaks of MEP facilitation were
consistently observed at interstimulus intervals of 1.1-1.5 ms, 2.3-2.7 ms, and 3.9-4.5
ms. The size of these MEP peaks was transiently suppressed by drugs which enhance
gamma-aminobutyric acid (GABA) function in the neocortex (lorazepam, vigabatrin,
phenobarbital, ethanol), while the GABA-B receptor agonist baclofen, anti-glutamate drugs
(gabapentin, memantine), and sodium channel blockers (carbamazepine, lamotrigine) had no
effect. The interstimulus intervals effective for the production of the MEP peaks remained
unaffected by all drugs. The MEP peaks are thought to be due to a facilitatory interaction
of I-(indirect) waves in the motor cortex. Therefore, the present results indicate that
the production of I-waves is primarily controlled by GABA related neuronal circuits. The
potential relevance of this non-invasive paired TMS protocol for the investigation of
I-waves in patients with neurological disease will be discussed. Publication Types:
Clinical trial PMID: 9751295, UI: 98421915 Z Gastroenterol 1998 Jul;36(7):559-66 [ETICS Study: Empirical
therapy of idiopathic chronic singultus]. [Article in German] Petroianu G, Hein G,
Petroianu A, Bergler W, Rufer R Institut fur Pharmakologie und Toxikologie, Fakultat fur
Klinische Medizin Mannheim, Universitat Heidelberg. Idiopathic chronic singultus (ICS)
describes recurring episodes of persistent hiccuping lasting longer than an arbitrary time
limit (e.g. one month) for which no organic cause or consistently effective treatment can
be found. It has been suggested that ICS may result from chronic stimulation of a
supraspinal "hiccup center" by impulses originating from receptors in the
gastrointestinaltract. This hypotesis implies the possibility of treating ICS by reducing
gastric acid (via omeprazole), facilitating gastric emptying (via cisapride), or
suppressing of the "hiccup centre" (via GABA-ergic offects of baclofen or
gabapentin). 29 patients (28 male, one female; age 71 +/- 10 years) suffering from ICS for
four to 564 months were treated with a combination of cisapride (30 mg/d), omeprazole (20
mg/d) and baclofen (45 mg/d) (COB). The patients rated the severity of hiccuping on a
subjective assessment scale (SAS) that ranged from 0 (= no hiccuping) to 10 (= unbearable
hiccuping). Hiccuping ceased in 38% (11/29) of the treated patients and decreased in
severity in an additional 24% (7/29). Mean SAS-scores following 20 to 24 weeks of therapy
(3.7 +/- 3.4) were significantly lower compared to before therapy (8.8 +/- 1.3)
(Mann-Whitney rank order test [p < 0.02]). In the patients that failed to respond to
COB, gabapentin (1.200 mg/d) was substituted for baclofen. Hiccuping ceased in one and
improved in two of these ten subjects. We conclude that COB is an effective empirical
therapy in the majority of patients with ICS. It may be useful to substitute gabapentin
for baclofen in those not responding to COB. PMID: 9738303, UI: 98410046 Mov Disord 1998 Sep;13(5):829-31 Effective treatment of orthostatic tremor with gabapentin. Evidente VG, Adler CH, Caviness JN, Gwinn KA Parkinson's Disease and Movement
Disorders Center, Mayo Clinic Scottsdale, Arizona 85259, USA. We report seven patients with orthostatic tremor (OT) who were successfully treated
with the anticonvulsant gabapentin. Five of the patients had been previously tried on
clonazepam, the most commonly used drug for OT, four without any benefit. The degree of
improvement perceived by the patients with gabapentin varied from 60-80% (mean 73%). The
effective dose of gabapentin ranged from 300-1800 mg/day (mean 1030 mg/day). The side
effects were generally mild, transient, and dose-related. Duration of response has so far
ranged from 2-22 months (mean 11 months) with all patients still currently benefiting from
gabapentin. We conclude that gabapentin may be an effective treatment for OT. Further
trials are indicated. PMID: 9756154, UI: 98427585 Neurology 1998 Sep;51(3):880-2 Gabapentin in orthostatic tremor: results of a double-blind crossover with placebo
in four patients. Onofrj M, Thomas A, Paci C, D'Andreamatteo G Department
of Oncology and Neuroscience, University G. D'Annunzio Chieti, Italy. We treated four
patients affected by orthostatic tremor (OT) with gabapentin in increasing doses (300 to
2,400 mg/d). OT was evaluated with patients' self-monitoring scales, tremor rating scales,
electromyography (EMG) showing the 14- to 18-Hz frequencies, and EMG frequency analysis.
All patients had transitory responses to clonazepam. Gabapentin induced disappearance of
OT in three patients and consistent reduction in one. Crossover to placebo induced
reappearance of tremor. PMID: 9748048, UI: 98418844 J Biol Chem 1998 Sep 25;273(39):25458-65 Cloning and deletion mutagenesis of the alpha2delta calcium channel subunit
from porcine cerebral cortex. Expression Of a soluble form of the protein that retains
[3h]gabapentin binding activity. Brown JP, Gee NS Parke-Davis Neuroscience
Research Centre, Cambridge University Forvie Site, Robinson Way, Cambridge, CB2 2QB,
United Kingdom. The anti-epileptic, anti-hyperalgesic, and anxiolytic agent gabapentin
(1-(aminomethyl)-cyclohexane acetic acid or Neurontin) has previously been shown to bind
with high affinity to the alpha2delta subunit of voltage-dependent calcium channels (Gee,
N. S. , Brown, J. P., Dissanayake, V. U. K., Offord, J., Thurlow, R., and Woodruff, G.N.
(1996) J. Biol. Chem. 271, 5768-5776). We report here the cloning, sequencing, and
deletion mutagenesis of the alpha2delta subunit from porcine brain. The deduced protein
sequence has a 95.9 and 98.2% identity to the rat and human neuronal alpha2delta
sequences, respectively. [3H]Gabapentin binds with a KD of 37.5 +/- 10.4 nM to membranes
prepared from COS-7 cells transfected with wild-type porcine alpha2delta cDNA. Six
deletion mutants (B-G) that lack the delta polypeptide, together with varying amounts of
the alpha2 component, failed to bind [3H]gabapentin. C-terminal deletion mutagenesis of
the delta polypeptide identified a segment (residues 960-994) required for correct
assembly of the [3H]gabapentin binding pocket. Mutant L, which lacks the putative membrane
anchor in the delta sequence, was found in both membrane-associated and soluble secreted
forms. The soluble form was not proteolytically cleaved into separate alpha2 and delta
chains but still retained a high affinity (KD = 30.7 +/- 8.1 nM) for [3H]gabapentin. The
production of a soluble alpha2delta mutant supports the single transmembrane model of the
alpha2delta subunit and is an important step toward the large-scale recombinant expression
of the protein. PMID: 9738015, UI: 98411353 J Inherit Metab Dis 1998 Aug;21(5):587-97 Mutant CuZn superoxide dismutase in motor neuron disease.
Gurney ME, Liu R, Althaus JS, Hall ED, Becker DA Pharmacia & Upjohn, Inc. Central
Nervous System Diseases Research, Kalamazoo, Michigan, USA. CuZn superoxide dismutase
(CuZn SOD) is one of several antioxidant enzymes that defend the cell against damage by
oxygen free radicals. Mutations of the SOD1 gene encoding CuZn SOD are found in patients
with familial amyotrophic lateral sclerosis (FALS), a progressive and fatal paralytic
disease that is caused by the death of motor neurons in cortex, brainstem and spinal cord.
The disease can be reproduced in transgenic mice by expression of mutant human CuZn SOD.
Recent studies both in vitro and in vivo suggest that the effect of mutation is to enhance
the generation of oxygen radicals by the mutant enzyme. Thus, mutation converts a
protective, antioxidant enzyme into a destructive, prooxidant form that catalyses free
radical damage to which motor neurons are selectively vulnerable. Recent studies of
neuroprotective agents in the FALS model show that inhibition of oxidative mechanisms
(copper chelation therapy, dietary antioxidants, and coexpression of bcl-2) delays disease
onset but does not extend disease duration. In contrast, inhibition of glutamatergic or
apoptotic mechanisms (riluzole, gabapentin, and coexpression of glutamatergic or apoptotic
mechanisms (riluzole, gabapentin, and coexpression of an inhibitor of caspase-1) has no
effect on disease onset but extends survival by increasing the duration of symptomatic
disease. Thus, neuroprotective agents differentially target the processes underlying
disease initiation and propagation. PMID: 9728338, UI: 98397584 J Clin Psychiatry 1998 Aug;59(8):426-9 Gabapentin treatment of mood disorders: a preliminary study. Ghaemi
SN, Katzow JJ, Desai SP, Goodwin FK Psychopharmacology Research Center, Department of
Psychiatry, The George Washington University, Washington, DC 20037, USA. OBJECTIVE: To
determine if gabapentin is effective either as adjunctive treatment or as monotherapy for
major affective disorders in a naturalistic setting. METHOD: All charts of patients
meeting DSM-IV criteria for bipolar disorder or unipolar major depressive disorder treated
with gabapentin in a private psychiatric practice were reviewed and clinical response was
assessed retrospectively using the Clinical Global Impressions scale for Improvement
(CGI-I). RESULTS: Gabapentin was moderately to markedly effective in 30% (15/50) of
patients, with statistically nonsignificant differences between patients with bipolar
disorder type I, bipolar disorder type II and NOS, and unipolar major depressive disorder.
70% reported side effects, mainly sedation, with 16% of the total sample discontinuing
treatment due to adverse events. CONCLUSION: Gabapentin appears to be somewhat effective
as add-on treatment in a subgroup of patients with mood disorders in a naturalistic
setting. Prospective, controlled studies are required to clarify these pilot data. PMID:
9721823, UI: 98387278 South Med J 1998 Aug;91(8):739-44 Gabapentin for treatment of pain and tremor: a large case series.
Merren MD Neurology Clinic of San Antonio, TX 78229, USA. BACKGROUND: Several
anticonvulsant agents, including carbamazepine, phenytoin, and valproate, are effective in
some patients for the treatment of pain and tremor. This study reports on a trial of the
newly introduced anticonvulsant, gabapentin, for pain and tremor control. METHODS: A large
case series of patients with centrally mediated pain, peripherally mediated pain,
migraine, and tremor were treated in an open-label study with gabapentin (maximum of 2,700
mg/day). RESULTS: Thirty-nine patients (65%) had moderate-to-excellent improvement in
symptoms, with the best responses occurring in patients with peripherally mediated
neuropathic pain. The other conditions treated that showed some improvement were benign
essential/familial tremor, restless legs syndrome, centrally mediated pain, and periodic
nighttime leg movements. CONCLUSIONS: Gabapentin offers an effective, safe alternative
therapy or co-therapy for the listed painful conditions and tremor; it does not affect the
metabolism of other medications and is well tolerated. Publication Types: * Clinical trial
PMID: 9715219, UI: 98380951 Epilepsy Res 1998 Jul;31(2):91-9 Gabapentin bioavailability: effect of dose and frequency of administration in
adult patients with epilepsy. Gidal BE, DeCerce J, Bockbrader HN, Gonzalez
J, Kruger S, Pitterle ME, Rutecki P, Ramsay RE School of Pharmacy, University of
Wisconsin, Madison 53706, USA. beg@pharmacy.wisc.edu Gabapentin (GBP) is a non-metabolized
antiepileptic drug that is eliminated by renal excretion and displays saturable, dose
dependent absorption. The recommended dosing schedule for GBP is t.i.d. At large daily
doses, oral bioavailability (F) may be improved by giving the daily dose more frequently.
OBJECTIVE: To evaluate whether switching GBP dosage regimen from t.i.d. to q.i.d. results
in increased oral bioavailability. METHODS: This study consisted of two parts; a computer
simulated pharmacokinetic model and a clinical pharmacokinetic study in nine adult
epileptic patients receiving 3600 mg/day and 11 receiving 4800 mg/day. All patients were
evaluated during both t.i.d. and q.i.d. regimens. F were determined by calculation of
percent of dose excreted unchanged using steady-state 24-h urine collections and were
compared using a paired t-test. RESULTS: At 3600 mg/day, mean F following t.i.d. and
q.i.d. dosing were 38.7+/-22.1% and 40.0+/-18.9%, respectively (P=0.738). At 4800 mg/day,
mean F following t.i.d. and q.i.d. dosing were 29.2+/-16.2% and 35.6+/-17.6%, respectively
(P=0.006). DISCUSSION: Good agreement was observed between values from this study and
predicted values based on the pharmacokinetic model. Improved GBP F at doses of 3600
mg/day was not achieved with more frequent drug administration, and thus is not warranted.
At 4800 mg/day, a 22% increase in F was observed with more frequent drug dosing.
CONCLUSION: GBP F may be significantly increased by q.i.d. versus t.i.d. dosing, depending
upon dose level. This increase in F however must be balanced against the inconvenience of
more frequent dosing. Therapeutic drug level monitoring may aid in the evaluation of such
pharmacokinetic maneuvers. PMID: 9714500, UI: 98378302 Neurology 1998 Aug;51(2):611-4 Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients.
Khan OA Department of Neurology, University of Maryland School of Medicine, Veterans
Affairs Medical Center, Baltimore 21201, USA. This report describes the effectiveness of
gabapentin, a recently approved anticonvulsant, in seven patients with MS experiencing
trigeminal neuralgia refractory to treatment with conventional medical therapy. Gabapentin
relieved pain completely in six and significantly in the seventh patient. Gabapentin may
be a valuable addition to pharmacologic therapy in trigeminal neuralgia, particularly in
patients with MS and in refractory cases. PMID: 9710050, UI: 98373824 Neurology 1998 Aug;51(2):609-11 An open-label
trial of gabapentin treatment of paroxysmal symptoms in multiple sclerosis patients.
Solaro C, Lunardi GL, Capello E, Inglese M, Messmer Uccelli M, Uccelli A, Mancardi GL
Department of Neurological Sciences and Neurorehabilitation University of Genoa, Italy. We
conducted an open-label trial of gabapentin (GBP) as therapy for paroxysmal symptoms (PS)
in 21 MS patients, including trigeminal neuralgia (6 patients), painful tonic spasms (11),
dysesthetic or paresthetic symptoms (3) and ocular ataxia (1). Complete resolution of
symptoms or partial improvement was obtained, respectively, in 14 and 4 of 18 patients who
ended the study. Sustained improvement with minor side effects was obtained at dosages
ranging from 600 to 1200 mg/d. Our findings suggest that GBP may be effective for PS in MS
and warrant a further study in a double-blind placebo-controlled trial. PMID: 9710049, UI:
98373823 Clin Neuropharmacol 1998 Jul-Aug;21(4):215-35 The
efficacy and use of anticonvulsants in mood disorders.
Dunn RT, Frye MS, Kimbrell TA, Denicoff KD, Leverich GS, Post RM Biological Psychiatry
Branch, National Institute of Mental Health, Bethesda, Maryland 20892-1272, USA. Carbamazepine and valproate have utility in the acute and prophylactic treatment of
mood disorders that appears comparable with that of lithium, but there are emerging
differences as well, including responsiveness in some lithium-nonresponsive illness
subtypes. Carbamazepine and valproate are generally well tolerated, but each has its own
adverse effect profile and proclivity for pharmacokinetic interactions. The high potency
(anticonvulsant) benzodiazepines have utility in mood disorders as adjuncts to mood
stabilizers and often can obviate the need for neuroleptics. Several small studies suggest
that the dihydropyridine L-type calcium channel blockers can be useful mood stabilizers,
and several new antiepileptic agents, especially lamotrigine and gabapentin, may have
mood-stabilizing properties. The actions of electroconvulsive therapy as they relate to
activation of endogenous anticonvulsant processes, and the potential therapeutic effects
of nonconvulsive repeated transcranial magnetic stimulation of brain, are promising areas
of mood disorder research. PMID: 9704164, UI: 98369787 Pain 1998 May;76(1-2):201-7 Attenuation of formalin-induced nociceptive behaviors following local
peripheral injection of gabapentin. Carlton SM, Zhou S Department of
Anatomy and Neuroscience, Marine Biomedical Institute, University of Texas Medical Branch,
Galveston 77555-1069, USA. smcarlto@utmb.edu Gabapentin (GP) has been shown to have
antihyperalgesic properties and the site of drug action is reported to be the central
nervous system. The goal of the present study was to determine whether GP also has a
peripheral site of action. Rats received intraplantar 20-microl injections of 6, 60 or 600
microg GP + 2% formalin, 300 or 600 microg S-(+)-3-isobutylgaba + 2% formalin, 600 microg
R-(-)-3-isobutylgaba + 2% formalin or formalin alone. The two lower doses of GP
significantly reduced flinching and lifting/licking behavior during phase 2; however,
phase 1 behaviors were unaffected, 600 microg GP significantly reduced these nociceptive
behaviors during both phases. 600 microg S-(+)-3-isobutylgaba also reduced
formalin-induced nociceptive behaviors; however, 600 microg of the isomer
R-(-)-3-isobutylgaba had no effect. The antihyperalgesic effect of GP (1) was not due to a
systemic effect since animals injected with 600 microg GP in one hindpaw and 2% formalin
into the contralateral hindpaw developed nociceptive behaviors which were no different
than those seen in animals injected with formalin alone; (2) was not due to a local
anesthetic effect since needle sticks within the drug-injected region evoked paw
withdrawal behavior which was not different from pre-drug levels; (3) was blocked by 20
microl D-serine but not by L-serine. Although the mechanism of action of GP has yet to be
elucidated, these results indicate that GP has a peripheral site of action and thus may
offer a novel therapeutic agent for topical or local treatment of pain of peripheral
origin. PMID: 9696474, UI: 98359663 Epilepsy Res 1998 Jun;31(1):47-57 Gabapentin and carbamazepine affect eye movements and posture control differently:
a placebo-controlled investigation of acute CNS side effects in healthy volunteers.
Noachtar S, von Maydell B, Fuhry L, Buttner U Department of Neurology, University of
Munich, Germany. Noachtar@brain.nefo.med.uni-muenchen.de This prospective study examined
the effects of the new antiepileptic drug (AED) gabapentin (GBP) compared to the standard
AED carbamazepine (CBZ) and placebo (PLA) on eye movements, posture and finger force
control in 12 healthy volunteers who received single doses of 600 mg GBP and 400 mg CBZ in
a placebo-controlled, double-blind, cross-over, randomized trial. CBZ and GBP reduced
almost equally (8% vs. 10%) the mean peak saccade velocity as compared to PLA (P <
0.05). CBZ, but not GBP, significantly prolonged the duration of saccades as compared to
placebo (14-24%) (P < 0.05). GBP produced a greater maximal increase of body sway than
CBZ with eyes open (P < 0.01) and eyes closed (P < 0.001). CBZ and GBP did not
significantly influence control of grip force. CBZ effects were better correlated with
plasma levels. Subjective side effects were more pronounced with CBZ than GBP. Although
CBZ and GBP cause similar CNS side effects, the effects on eye movements and body sway
were different. CBZ predominantly affects saccadic eye movements, whereas GBP had more
impact on posture control. Thus, electro-oculography seems to be more appropriate in the
detection of CBZ-induced side effects and posturography appears to be more sensitive in
the detection of side effects associated with GBP. PMID: 9696300, UI: 98359489 Rev Neurol (Paris) 1997;153 Suppl 1:S39-45 Mechanisms of action of gabapentin. Taylor CP Department of
Neurological and Neurodegenerative Diseases, Parke-Davis Research Division, Ann Arbor,
Etats-Unis. The chemical structure of gabapentin (Neurontin) is derived by addition of a
cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents
seizures in a wide variety of models in animals, including generalized tonic-clonic and
partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake
carriers of brain. Gabapentin interacts with a high-affinity binding site in brain
membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive
Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and
remains under study. Gabapentin crosses several lipid membrane barriers via system L amino
acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme,
glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain
amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that
gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from
neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine
neurotransmitters. Gabapentin prevents pain responses in several animal models of
hyperalgesia and prevents neuronal death in vitro and in vivo with models of the
neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active
in models that detect anxiolytic activity. Although gabapentin may have several different
pharmacological actions, it appears that modulation of GABA synthesis and glutamate
synthesis may be important. Publication Types: * Review * Review, tutorial PMID: 9686247,
UI: 98350864 J Neurochem 1998 Aug;71(2):863-74 Role
of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter
metabolism. Hutson SM, Berkich D, Drown P, Xu B, Aschner M, LaNoue KF
Department of Biochemistry, Wake Forest University Medical School, Winston-Salem, North
Carolina 27157, USA. Because it is well known that excess branched-chain amino acids
(BCAAs) have a profound influence on neurological function, studies were conducted to
determine the impact of BCAAs on neuronal and astrocytic metabolism and on trafficking
between neurons and astrocytes. The first step in the metabolism of BCAAs is
transamination with alpha-ketoglutarate to form the branched-chain alpha-keto acids
(BCKAs). The brain is unique in that it expresses two separate branched-chain
aminotransferase (BCAT) isoenzymes. One is the common peripheral form [mitochondrial
(BCATm)], and the other [cytosolic (BCATc)] is unique to cerebral tissue, placenta, and
ovaries. Therefore, attempts were made to define the isoenzymes' spatial distribution and
whether they might play separate metabolic roles. Studies were conducted on primary rat
brain cell cultures enriched in either astroglia or neurons. The data show that over time
BCATm becomes the predominant isoenzyme in astrocyte cultures and that BCATc is prominent
in early neuronal cultures. The data also show that gabapentin, a structural analogue of
leucine with anticonvulsant properties, is a competitive inhibitor of BCATc but that it
does not inhibit BCATm. Metabolic studies indicated that BCAAs promote the efflux of
glutamine from astrocytes and that gabapentin can replace leucine as an exchange
substrate. Studying astrocyte-enriched cultures in the presence of [U-14C]glutamate we
found that BCKAs, but not BCAAs, stimulate glutamate transamination to alpha-ketoglutarate
and thus irreversible decarboxylation of glutamate to pyruvate and lactate, thereby
promoting glutamate oxidative breakdown. Oxidation of glutamate appeared to be largely
dependent on the presence of an alpha-keto acid acceptor for transamination in astrocyte
cultures and independent of astrocytic glutamate dehydrogenase activity. The data are
discussed in terms of a putative BCAA/BCKA shuttle, where BCATs and BCAAs provide the
amino group for glutamate synthesis from alpha-ketoglutarate via BCATm in astrocytes and
thereby promote glutamine transfer to neurons, whereas BCATc reaminates the amino acids in
neurons for another cycle. PMID: 9681479, UI: 98344804 Neuropharmacology 1998;37(1):83-91 Gabapentin inhibits calcium
currents in isolated rat brain neurons. Stefani A, Spadoni F, Bernardi G IRCCS Ospedale S.
Lucia, Rome, Italy. Stefani@UTOVRM.IT Gabapentin (1(aminomethyl) cyclohexane acetic acid;
GBP) is a recently developed anticonvulsant, for which the mechanism of action remains
quite elusive. Besides its possible interaction with glutamate synthesis and/or GABA
release, in cerebral membranes gabapentin has been shown to bind directly to the
alpha2delta subunit of the calcium channel. Therefore, we have tested the possibility that
gabapentin affects high threshold calcium currents in central neurons. Calcium currents
were recorded in whole-cell patch-clamp mode in neurons isolated from neocortex, striatum
and external globus pallidus of the adult rat brain. A large inhibition of calcium
currents by gabapentin was observed in pyramidal neocortical cells (up to 34%).
Significantly, the gabapentin-mediated inhibition of calcium currents saturated at
particularly low concentrations (around 10 microM), at least in neocortical neurons (IC50
about 4 microM). A less significant inhibition was seen in medium spiny neurons isolated
from striatum (-12.4%) and in large globus pallidus cells (-10.4%). In all these areas,
however, the GBP-induced block was fast and largely voltage-independent. Dihydropyridines
(nimodipine, nifedipine) prevented the gabapentin response. Omega-conotoxin GVIA and
omega-conotoxin MVIIC, known to interfere with the currents driven by alpha1b and alpha1a
calcium channels, did not prevent but partially reduced the response. These findings imply
that voltage-gated calcium channels, predominately the L-type channel, are a direct target
of gabapentin and may support its use in different clinical conditions, in which
intracellular calcium accumulation plays a central role in neuronal excitability and the
development of cellular damage. PMID: 9680261, UI: 98343855 Int J Clin Pharmacol Res 1998;18(2):93-100 Negative modultors of excitatory amino acids in episodic and chronic migraine:
preventing and reverting chronic migraine. Special lecture 7th inwin congress.
Nicolodi M, Sicuteri F Interuniversity Center of Neurochemistry, Florence University,
Italy. The mechanism capable of transforming episodic migraine into chronic migraine is
attributed by the authors to hyperalgesia and related neuroplastic changes, chiefly
long-term potentiation, due to the action of excitatory amino acids, chiefly the ones
acting at N-methyl D-aspartate (NMDA) receptor. A preeminent role has been attributed to
'third hyperalgesia', a newly observed type of hyperalgesia which is inheritable and can
act as a ground for the above-mentioned mechanism of 'chronicization' of migraine. The
role of primary and secondary hyperalgesia in giving redundance to neuraxial abnormalities
is also discussed. The fact that NMDA noncompetitive antagonist ketamine and gabapentin,
inhibitor of the neuronal synthesis of L-glutamate, can cure chronic migraine, so far
considered refractory to prophylactic therapies, gives indirect but evident support to the
mechanism suggested above. The antinociceptive role of the above-mentioned negative
modulators of excitatory amino acids and the possible interplay between ionotropic and
metabotropic receptors are also taken into consideration. PMID: 9675627, UI: 98340227 J Clin Psychiatry 1998;59 Suppl 6:74-81; discussion 82 Anticonvulsants and antipsychotics in the treatment of bipolar disorder.
Keck PE Jr, McElroy SL, Strakowski SM Department of Psychiatry, University of Cincinnati
College of Medicine, Ohio 45267-0559, USA. A number of recent advances in clinical
psychopharmacology regarding anticonvulsant and new antipsychotic medications have
important implications with respect to the treatment of patients who have bipolar
disorder. The authors reviewed the available literature on the efficacy of the
anticonvulsants valproate, carbamazepine, gabapentin, and lamotrigine for the treatment of
bipolar disorder. They also reviewed the use of standard and new antipsychotic medications
for the treatment of various aspects of the illness. Valproate and carbamazepine have been
shown to be effective in the treatment of acute mania in controlled trials. Preliminary
data suggest that these agents may differ in their time course of antimanic activity and
predictors of response. Neither agent has been extensively studied in controlled trials in
bipolar depression or as maintenance therapy, although carbamazepine has received the most
systematic study in these areas. Gabapentin and lamotrigine are only now being evaluated
in controlled trials in patients who have bipolar disorder. Antipsychotics are commonly
used in the treatment of patients with acute mania and as maintenance treatment. However,
the use of standard antipsychotics in acute mania is associated with a number of
limitations. New antipsychotic agents may possess thymoleptic as well as antipsychotic
activity, but they have not been studied in controlled trials in bipolar disorder.
Publication Types: * Review * Review, tutorial PMID: 9674940, UI: 98337697 J Clin Psychiatry 1998;59 Suppl 6:66-73 Special considerations: use of lithium in children, adolescents, and elderly
populations. Tueth MJ, Murphy TK, Evans DL Department of Psychiatry,
University of Florida College of Medicine, Gainesville, USA. Certain populations of
patients require special considerations when lithium is prescribed. Children and
adolescents have higher volumes of body water and more active renal glomerular filtration
rates than adults. Their central nervous system is developing and therefore is vulnerable
to the impact of substances, including medications such as lithium, that can cause side
effects or adverse events. Elderly patients have less body water, slower metabolism, and
often comorbid illnesses, so they also require close evaluation and monitoring when
prescribed lithium. This paper examines the indications for, pharmacokinetics of, clinical
uses of, and side effects of lithium in children, adolescents, and the elderly. Use of
alternate mood stabilizers is also addressed briefly. Publication Types: * Review *
Review, tutorial PMID: 9674939, UI: 98337696 Neuropsychopharmacology 1998 Sep;19(3):206-19 Beyond lithium in the treatment of bipolar illness. Post RM,
Frye MA, Denicoff KD, Leverich GS, Kimbrell TA, Dunn RT Biological Psychiatry Branch,
National Institute of Mental Health, Bethesda, Maryland 20892-1272, USA. Dramatic changes
have recently occurred in the availability of treatment options for bipolar illness.
Second generation mood stabilizing anticonvulsants carbamazepine and valproate are now
widely used as alternatives or adjuncts to lithium. High potency benzodiazepines are also
used as alternatives to typical neuroleptics, and now atypical neuroleptics are
demonstrating efficacy and better side-effects profiles than the typicals. Thyroid
augmentation strategies and dihydropyridine L-type calcium channel blockers require
further clinical trials to define their role. Putative third generation mood stabilizing
anticonvulsants lamotrigine, gabapentin, and topiramate have unique mechanisms of action
and deserve further systematic study, as does the potential role for nonconvulsive brain
stimulation with repeated transcranial magnetic stimulation (rTMS). These and a host of
other potential treatment options now require a new generation of clinical trials to help
identify clinical and biological markers of response and optimal use alone and in complex
combination therapeutic regimens. Publication Types: * Review * Review, academic PMID:
9653709, UI: 98317596 Psychopharmacology (Berl) 1998 May;137(1):74-80 Reduction of 3,4-diaminopyridine-induced biogenic amine synthesis and release
in rat brain by gabapentin. Pugsley TA, Whetzel SZ, Dooley DJ Psychiatric
Disorders Therapeutics, Parke-Davis Pharmaceutical Research, Warner-Lambert Co., Ann
Arbor, MI 48105, USA. The anticonvulsant drug gabapentin has been shown recently to
exhibit anxiolytic and analgesic actions in animals. Such actions have been postulated in
part to reflect effects on biogenic amine neuronal activity. Therefore the effects of
gabapentin on biogenic amine neuronal activity were assessed by measuring the synthesis of
norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in rat brain and on the release of
[3H] NE from rat hippocampal slices both in the presence and absence of the depolarizing
agent 3,4-diaminopyridine (DAP). Gabapentin (30 and 100 mg/kg, i.p.) did not alter the
basal synthesis rates of NE and DA as assessed by the unchanged accumulation of
L-dihydroxyphenylalanine (DOPA) in the NE-enriched hippocampus and cortex and in the
DA-enriched striatum and mesolimbic areas. Gabapentin also did not alter 5-HT synthesis as
determined by the unaltered accumulation of 5-hydroxytryptophan (5-HTP) in the same brain
areas. DAP (2 mg/kg, i.p.) induced a modest but significant increase in DOPA accumulation
in the hippocampal, mesolimbic and striatal regions. This DAP-induced increase in DOPA
accumulation was antagonized significantly in the hippocampus and mesolimbic regions by
gabapentin at 30 and 100 mg/kg and in striatum by 100 mg/kg; a 10 mg/kg dose was inactive.
DAP increased selectively 5-HT synthesis in hippocampus and this effect was blocked by
gabapentin. These findings indicate that the increased synthesis of biogenic amines
induced by DAP is antagonized by gabapentin. In support of the in vivo studies, gabapentin
was also shown to inhibit the DAP-evoked release of [3H]NE from hippocampal slices.
Although the underlying mechanism for these effects is unclear, the present findings
nevertheless demonstrate that gabapentin has inhibitory effects on stimulated NE, DA and
5-HT neurons that may be involved in explaining in part the CNS effects of this drug.
PMID: 9631959, UI: 98293720 J Affect Disord 1998 Jun;49(3):229-33 Clinical experience using gabapentin adjunctively in patients with a history of
mania or hypomania. Knoll J, Stegman K, Suppes T University of Texas
Southwestern Medical Center at Dallas, USA. BACKGROUND: Gabapentin is an anticonvulsant
proposed to have mood-stabilizing properties. It has been effective in the add-on
treatment of refractory partial seizures and secondary generalized tonic-clonic seizures.
It has the advantage of a favorable side effect profile and lack of drug interactions.
METHODS: Twelve consecutive outpatients with persistent, treatment-resistant bipolar
spectrum disorders were treated with gabapentin in combination with other medications.
Patients were started at 300 mg/day, which was titrated according to clinical response.
Response was assessed every 3-4 weeks with a Clinical Global Improvement Scale. Dosage and
side effects were noted. The median peak dose was 2400 mg/day. RESULTS: One patient had a
marked response to gabapentin; seven, a moderate response; two, mild; and two, no response
to treatment. Six patients discontinued treatment due to somatic complaints (i.e.,
sedation or fatigue). The most frequently reported adverse effect was sedation.
LIMITATIONS: Gabapentin was added openly, and rating was nonblind in this case series. The
use of concomitant medications could have increased the amount of sedation experienced
with gabapentin. CONCLUSION: Overall, gabapentin was associated with moderate improvement
of mood symptoms. Given the severity and chronicity of these patients' illness, a moderate
response must be considered a relative success. Controlled studies of gabapentin are
needed to clarify its role in the treatment of bipolar disorder. PMID: 9629953, UI:
98291905 Mov Disord 1998 May;13(3):465-7 Double-blind
controlled trial of gabapentin in essential tremor. Pahwa R, Lyons K,
Hubble JP, Busenbark K, Rienerth JD, Pahwa A, Koller WC Department of Neurology,
University of Kansas Medical Center, Kansas City 66160, USA. Gabapentin has been reported
to be effective for essential tremor (ET) based on open-label trials. We studied
gabapentin (1800 mg/day) and placebo in a double-blind crossover design in 20 ET patients.
Eighteen patients completed the study and two patients dropped out as a result of adverse
effects which resolved when the medication was discontinued. Tremor was assessed at
baseline and after 2 weeks of gabapentin and placebo treatment. One patient was mildly
improved and another was moderately improved with placebo. Similarly, one patient reported
mild improvement and another patient had marked improvement with gabapentin. All the
remaining patients either reported no change or were worse with both treatment arms. There
was no significant difference for total tremor score, hand tremor score, handwriting
scores, or pouring scores. Sickness Impact Profile scores were no different between
placebo and gabapentin. Our results suggest that as an adjuvant therapy in ET, gabapentin
has limited benefit. Publication Types: * Clinical trial * Randomized controlled trial
PMID: 9613738, UI: 98273794 Neurology 1998 Apr;50(4):1146-1148 Gabapentin does not interact with a
contraceptive regimen of norethindrone acetate and ethinyl estradiol. Eldon MA, Underwood BA, Randinitis EJ, Sedman AJ Department of Clinical Pharmacology, Parke-Davis, Pharmaceutical Research Division,
Warner-Lambert Co., Ann Arbor, MI, USA. Anticonvulsants that induce hepatic metabolism increase clearance of oral contraceptive
hormones and thereby cause contraceptive failure. Gabapentin is not metabolized in humans
and has little liability for causing metabolic-based drug-drug interactions. In healthy
women receiving 2.5 mg norethindrone acetate and 50 microg ethinyl estradiol daily for
three consecutive menstrual cycles, concurrent gabapentin administration did not alter the
steady-state pharmacokinetics of either hormone. Thus, gabapentin is unlikely to cause
contraceptive failure. Publication Types: Clinical trial PMID: 9566412, UI: 98226063 Ann Pharmacother 1998 Apr;32(4):405-409 Gabapentin absorption: effect of
mixing with foods of varying macronutrient composition. Gidal BE, Maly MM, Kowalski JW, Rutecki PA, Pitterle ME, Cook DE School of Pharmacy and Department of Neurology, University of Wisconsin, Madison 53706,
USA. BEG@pharmacy.wisc.edu OBJECTIVE: To compare the oral absorption profile of gabapentin following
administration of the contents of opened capsules that were mixed with food vehicles of
varied macronutrient (protein) composition. DESIGN: An unblinded, randomized, single-dose, four-way crossover pharmacokinetic study
in nine healthy adult men and women volunteers. METHODS: Following an overnight fast, a single 600-mg dose of gabapentin (2 x 300-mg
Neurontin capsules) was given either as an intact capsule swallowed with 120 mL of tap
water (control, phase I), or after capsule contents were opened and mixed with; 4 oz. of
applesauce (phase II), 120 mL of orange juice (phase III), or 4 oz. of fat-free chocolate
pudding (phase IV). Subjects fasted for 4 hours following drug ingestion. Serial venous
blood samples were obtained over 24 hours to determine gabapentin serum concentrations.
Pharmacokinetic variables including AUC, maximum serum concentration (Cmax), and time to
maximum serum concentration (tmax) were calculated by using standard noncompartmental
methods. Subjects served as their own controls, and were randomly crossed over following a
minimum 7-day washout period. Statistical analysis was performed by using ANOVA and
Student's t-test where appropriate. RESULTS: No statistically significant differences in any kinetic variable were found
between any study arm. A trend was noted for a modest increase in both Cmax and AUC in
phase IV (chocolate pudding) compared with control (+18.6% and +13.2%, respectively). In a
comparison of protein (phase IV) versus nonprotein phases (phases I-III), gabapentin AUC
was 26% greater (47.28+/-14.65 vs. 37.43+/-9.78 microg/mL x h; p = 0.03), and Cmax was 32%
higher (4.72+/-1.04 vs. 3.56+/-0.92 microg/mL; p = 0.003). CONCLUSIONS: Opening and mixing the contents of gabapentin capsules does not
significantly impair drug absorption. This may be a viable administration option for
patients who are unable to swallow intact capsules. Dietary macronutrient composition
(i.e., protein) may favorably influence gabapentin oral absorption. PMID: 9562133, UI: 98220602 Seizure 1997 Dec;6(6):503-504 Isolated ataxia as an idiosyncratic
side-effect under gabapentin. Steinhoff BJ, Herrendorf G, Bittermann HJ, Kurth C Department of Clinical Neurophysiology, Georg-August University, Gottingen, Germany. Gabapentin has been accepted worldwide as a novel antiepileptic drug with a favourable
tolerability profile. However, movement disorders have been reported previously as rare
side-effects in individual patients. We report on two patients who developed isolated
severe ataxia under low-dose gabapentin which resolved abruptly after discontinuation of
the drug. This side-effect probably resembled a rare idiosyncratic adverse reaction. We
propose the gabapentin-specific neuronal binding site which has a high density in the
cerebellum as a possible mechanism of action and suggest that the initiation of gabapentin
requires caution if pre-existing cerebellar function impairment is evident. PMID: 9530950, UI: 98189433 Pain 1998 Feb;74(2-3):341-343 Gabapentin induced polyneuropathy. Gould HJ Department of Neurology, LSU Medical Center, New Orleans, LA 70112, USA. Gabapentin is an effective option for the treatment of neuropathic pain syndromes
because of its efficacy and favorable side-effect profile. A case is presented of a 58
year old man who developed a painful polyneuropathy while being treated with gabapentin. PMID: 9520250, UI: 98179072 Epilepsy Res 1998 Feb;29(3):233-249 A summary of mechanistic hypotheses of
gabapentin pharmacology. Taylor CP, Gee NS, Su TZ, Kocsis JD, Welty DF, Brown JP, Dooley DJ, Boden P, Singh L
Department of Neuroscience Therapeutics, Parke-Davis Pharmaceutical Research, Division of
Warner-Lambert Co., Ann Arbor, MI 48105, USA. Although the cellular mechanisms of pharmacological actions of gabapentin (Neurontin)
remain incompletely described, several hypotheses have been proposed. It is possible that
different mechanisms account for anticonvulsant, antinociceptive, anxiolytic and
neuroprotective activity in animal models. Gabapentin is an amino acid, with a mechanism that differs from those of other
anticonvulsant drugs such as phenytoin, carbamazepine or valproate. Radiotracer studies
with [14C]gabapentin suggest that gabapentin is rapidly accessible to brain cell cytosol.
Several hypotheses of cellular mechanisms have been proposed to explain the pharmacology
of gabapentin: 1. Gabapentin crosses several membrane barriers in the body via a specific amino acid
transporter (system L) and competes with leucine, isoleucine, valine and phenylalanine for
transport. 2. Gabapentin increases the concentration and probably the rate of synthesis of GABA in
brain, which may enhance non-vesicular GABA release during seizures. 3. Gabapentin binds with high affinity to a novel binding site in brain tissues that is
associated with an auxiliary subunit of voltage-sensitive Ca2+ channels. Recent
electrophysiology results suggest that gabapentin may modulate certain types of Ca2+
current. 4. Gabapentin reduces the release of several monoamine neurotransmitters. 5. Electrophysiology suggests that gabapentin inhibits voltage-activated Na+ channels,
but other results contradict these findings. 6. Gabapentin increases serotonin concentrations in human whole blood, which may be
relevant to neurobehavioral actions. 7. Gabapentin prevents neuronal death in several models including those designed to
mimic amyotrophic lateral sclerosis (ALS). This may occur by inhibition of glutamate
synthesis by branched-chain amino acid aminotransferase (BCAA-t). Anesth Analg 1998 Feb;86(2):348-354 The effect of intrathecal gabapentin
and 3-isobutyl gamma-aminobutyric acid on the hyperalgesia observed after thermal injury
in the rat. Jun JH, Yaksh TL Department of Anesthesiology, Hanyang University College of Medicine,
Seoul, Korea. Gabapentin is an anticonvulsant that may represent a novel class of drugs, which has
novel spinal antihyperalgesic activity. We sought to characterize this spinal action in a
model of hyperalgesia that involves a mild thermal injury to the hind paw of the rat. Rats
were prepared with chronic spinal catheters. Under brief halothane anesthesia, a thermal
injury was induced by applying the left hind paw to a thermal surface (52.5 degrees C) for
45 s. This exposure results in mild erythema but no blistering. Thermal escape latency of
the hind paw was determined using an underglass thermal stimulus with which response
latencies of the injured and uninjured (normal) paw could be obtained. Thirty minutes
after thermal injury, the response latency in all groups decreased from 10-12 s to 5-7 s.
Uninjured paw withdrawal latency was unaltered. The intrathecal injection of gabapentin
(30-300 microg) produced a dose-dependent reversal of the hyperalgesia but had no effect
on the response latency of the normal hind paw, even at the largest doses. A similar
reversal was observed after intrathecal delivery of the structural analog S(+)-3-isobutyl
gamma-aminobutyric acid (GABA) (30-300 microg), but not after the largest dose of its
stereoisomer R(-)-3-isobutyl GABA (300 microg). The effects of both intrathecal gabapentin
and S(+)-3-isobutyl GABA were reversed by intrathecal D-serine, but not L-serine. All
effects were observed at doses that had no significant effect on motor function. These observations, in conjunction with the accumulating data on binding and
transmitter release, emphasize that these gabapentinoids can selectively modulate the
facilitation of spinal nociceptive processing otherwise generated by persistent small
afferent input generated by tissue injury. Implications: Gabapentin and its analog, 3-isobutyl gamma-aminobutyric acid, given
spinally, produce a dose-dependent, D-serine-sensitive reversal of the thermal
hyperalgesia evoked by mild thermal injury. Anesthesiology 1998 Jan;88(1):196-205 Characterization of the effects of
gabapentin and 3-isobutyl-gamma-aminobutyric acid on substance P-induced thermal
hyperalgesia. Partridge BJ, Chaplan SR, Sakamoto E, Yaksh TL Department of Anesthesiology, University
of California, San Diego, La Jolla 92093-0818, USA. BACKGROUND: The authors sought to characterize the pharmacologic characteristic and
site of action of gabapentin (Neurontin) in a model of thermal hyperalgesia induced by
intrathecal substance P administration. METHODS: Rats were prepared with long-term lumbar intrathecal catheters. Hind paw
withdrawal latency was determined using a radiant heat stimulus focused through a glass
surface onto the plantar surface of the paw. RESULTS: Within 5 min after intrathecal injection of substance P (30 nmol), hind paw
withdrawal latency fell from 11 to 8 s. Gabapentin given intrathecally or
intraperitoneally produced dose-dependent reversal of the thermal hyperalgesia, with
complete reversal (ED100) occurring at 163 microg for intrathecal and 185 mg/kg for
intraperitoneal administration. S(+)-3-isobutyl-gamma aminobutyric acid, but not
R(-)-3-isobutyl-gamma aminobutyric acid, also produced dose-dependent reversal of the
intrathecal substance P-induced thermal hyperalgesia (intrathecal ED100, 65 microg and
intraperitonal ED100, 31 mg/kg). The effects of intraperitoneally administered gabapentin
and 3-isobutyl-gamma aminobutyric acid were reversed by intrathecal pretreatment with
D-serine (100 microg) but not by L-serine. All effects were observed at doses that had
little effect on motor function or spontaneous activity. Intrathecal N-methyl-D-aspartate
(2 nmol) induced thermal hyperalgesia, which was blocked by gabapentin (100 mg/kg
intraperitoneally) and S(+)-3-isobutyl-gamma aminobutyric acid (30 mg/kg
intraperitoneally). CONCLUSIONS: The structure-activity relationship and the stereospecificity noted after
intrathecal delivery suggest that gabapentin and S(+)-3-isobutyl-gamma aminobutyric acid
act at a common spinal locus to modulate selectively a facilitated state of nociceptive
processing. Am J Psychiatry 1998 Jan;155(1):12-21 Mood stabilizer combinations: a review
of safety and efficacy. Freeman MP, Stoll AL Psychopharmacology Unit, Division of Psychiatry, Brigham and
Women's Hospital, Boston, MA 02115, USA. mpfreeman@bics.bwh.harvard.edu OBJECTIVE: Polypharmacy is common in the treatment of refractory bipolar disorder. The
purpose of this article is to review the safety and efficacy of mood stabilizers in
combinations. METHOD: A manual and computer (MEDLINE) search was performed for combinations of the
most commonly used mood-stabilizing agents. RESULTS: The authors review safety and efficacy data on the more frequently encountered
combinations of established and putative mood stabilizers. CONCLUSIONS: There have been few controlled studies of the use of combinations of mood
stabilizers. The interactions of such combinations are sometimes complex, often very
useful, and potentially dangerous. One general rule that may reduce the risks of toxic
drug interactions is to add medication to the patient's current regimen in modest doses
and increase the dose slowly. The safest and most efficacious mood stabilizer combinations
appear to be the mixtures of anticonvulsants and lithium, particularly valproate plus
lithium. Once the mechanisms of the mood stabilizers are identified, it is possible that a
more rational approach to combination therapy will emerge, based on synergism at the sites
of action. Anesth Analg 1998 Jan;86(1):111-116 Gabapentin reverses the allodynia
produced by the administration of anti-GD2 ganglioside, an immunotherapeutic drug.
Gillin S, Sorkin LS Department of Anesthesiology, University of California-San Diego,
La Jolla 92093-0818, USA. Systemically administered, the anti-GD2 antibody produces allodynia demonstrated by
decreased mechanical withdrawal threshold. Electrophysiologic recordings indicate a
probable neuropathic origin, as small-diameter sensory fibers develop continuous
high-frequency discharge after antibody administration. Gabapentin (GBP) is a
gamma-aminobutyric acid analog originally synthesized for its anticonvulsant actions.
Several open-label clinical studies, as well as a wealth of anecdotal evidence, suggest
that GBP may be beneficial for the treatment of neuropathic pain. This study examined the
effects of GBP given as a posttreatment after induction of an anti-GD2-associated
allodynia. Anti-GD2 (1 mg/kg intravenously [i.v.]) administered to Sprague-Dawley rats
reduced the mean withdrawal threshold from 14.71 to 4.95 g (P < 0.001), as measured by
using von Frey hairs. This was reversed by GBP in a dose-dependent fashion; the minimal
effective dose was between 3 and 30 mg/kg i.v. The maximal percent analgesic effect of GBP
was 76% and 93% at doses of 30 and 100 mg/kg, respectively (P < 0.001). With these
doses, side effects were minimal and were manifested as slightly decreased spontaneous
movement and startle response. No changes were seen in reflex responses to corneal or
pinna stimulation, and no motor deficits were observed. These data support the use of GBP
as an effective therapy for neuropathic pain. Implications: After the administration of
anti-GD2 antibody, rats display an escape reaction to light touch, increased blood
pressure, and aberrant firing in nerve fibers associated with pain transmission. Systemic
gabapentin reduced or eliminated the escape response and reversed the hypertension with
minimal side effects. This suggests that gabapentin blocked the antibody-associated
(neuropathic) pain. Mult Scler 1997 Aug;3(4):250-253 Open label gabapentin treatment for pain
in multiple sclerosis. Houtchens MK, Richert JR, Sami A, Rose JW Neurovirology Research Laboratory, VAMC, Salt
Lake City, Utah, USA. Pain is a frequent and distressing complaint in patients with multiple sclerosis (MS)
and may present a difficult therapeutic problem. Conventional therapy is moderately
effective and includes, among others, a variety of anticonvulsant medications. Gabapentin
(Neurontin) is a new generation antiepileptic drug which appears to be advantageous in
treatment of intractable pain of reflex sympathetic dystrophy. This study investigates the
benefits of open-label treatment with gabapentin for pain control in 25 patients with MS. Excellent to moderate pain relief was obtained in a substantial number of patients.
Throbbing pains and needles, and cramping pains responded best, and dull aching pains
responded least to the medication. There was no significant change in distribution and
type of pain as a result of this treatment. Mild to moderate side effects were observed.
Cautious escalation of the dose of gabapentin is advisable in MS patients. Further
clinical trials with larger patient groups are recommended. Neurology 1997 Nov;49(5):1441-1442 Gabapentin for familial paroxysmal dystonic choreoathetosis. Chudnow RS, Mimbela RA, Owen DB, Roach ES Department of Neurology, UT Southwestern
Medical Center, Dallas, TX 75235-7794, USA. We present a 4-year-old girl with stereotyped episodes of inability to speak and
dystonic posturing of the face and extremities lasting 20 minutes. An older brother and
mother had similar spells in childhood. Routine and video-EEG during events were normal.
The diagnosis was non-kinesigenic paroxysmal dystonic choreoathetosis since the episodes
were not exacerbated by movement. Gabapentin 10 mg/kg/d eliminated most attacks. Int J Clin Pharmacol Res 1997;17(2-3):97-100 Modulation of excitatory amino acids
pathway: a possible therapeutic approach to chronic daily headache associated with
analgesic drugs abuse. Nicolodi M, Del Bianco PL, Sicuteri F Interuniversity Centre of Neurochemistry and
Clinical Pharmacology of Idiopathic Headache, University of Florence, Italy. The use of antagonists of N-methyl-D-aspartate (NMDA) receptors, or the administration
of inhibitors of the synthesis or of the release of excitatory amino acids, enables the
analgesic drug-dependence associated with chronic daily migraine to be overcome without
any physical abstinence sign. Follow-up period indicates that negative modulators of
excitatory amino-acid function can induce a stable benefit. The persistent benefit is
seemingly due to an inhibitory effect on the process underlying the hyperalgesia state
which is a crucial feature of migraine. It can also be suggested that the antagonist
activity at NMDA receptor might play a role in very severe non-opioid analgesic drug
dependence. Reg Anesth 1997 Sep;22(5):473-478 Experience with gabapentin for
neuropathic pain in the head and neck: report of ten cases. Sist TC, Filadora VA 2nd, Miner M, Lema M Department of Anesthesiology, Roswell Park
Cancer Institute, Buffalo, NY 14263, USA. BACKGROUND AND OBJECTIVES: Gabapentin is an oral antiepileptic agent with an unknown
mechanism of action. Recent case reports have suggested that gabapentin may be effective
in the treatment of a variety of neuropathic pain states. This report presents baseline
and follow-up data on ten patients who were treated with gabapentin when other
pharmacologic interventions failed to relieve their neuropathic pain. METHODS: Ten patients referred for treatment of unrelieved neuropathic pain in the head
and neck region were included in this study. Baseline and follow-up information included
measures of pain intensity and pain quality. All of the patients were started on 300 mg
gabapentin three times per day, though daily doses of up to 2400 mg were required for pain
relief. RESULTS: Eight of the ten patients had no neuropathic pain on follow-up, whereas the
remaining 2 patients reported only partial relief at follow-up. None of the patients
complained of side effects. Gabapentin was effective in alleviating steady burning pain as
well as lancinating pain and allodynia. CONCLUSIONS: The results suggest that gabapentin may be effective in the management of
some cases of neuropathic pain in the head and neck. However, controlled, double-blind
longitudinal studies are needed to evaluate this possibility. J Pharmacol Exp Ther 1997 Sep;282(3):1242-1246 Evaluation of gabapentin and
S-(+)-3-isobutylgaba in a rat model of postoperative pain. Field MJ, Holloman EF, McCleary S, Hughes J, Singh L Department of Biology, Parke-Davis
Neuroscience Research Centre, Cambridge University Forvie Site, United Kingdom. Gabapentin and S-(+)-3-isobutylgaba are anticonvulsant agents that selectively interact
with the alpha2delta subunit of voltage-dependent calcium channels. This report describes
the activities of these two compounds in a rat model of postoperative pain. An incision of
the plantaris muscle of a hind paw induced thermal hyperalgesia and tactile allodynia
lasting at least 3 days. Postoperative testing was carried out using the plantar test for
thermal hyperalgesia and von Frey hairs for tactile allodynia. A single s.c. dose of
gabapentin, 1 h before surgery, dose-dependently (3-30 mg/kg) blocked the development of
allodynia and hyperalgesia with a minimum effective dose (MED) of 10 and 30 mg/kg,
respectively. The highest dose of gabapentin prevented development of hyperalgesia and allodynia for
24 and 49 h, respectively. Similar administration of S-(+)-3-isobutylgaba also
dose-dependently (3-30 mg/kg, s.c.) prevented development of hyperalgesia and allodynia
with MED of 3 and 10 mg/kg, respectively. The highest dose of S-(+)-3-isobutylgaba
completely blocked development of both nociceptive responses for 3 days. The
administration of S-(+)-3-isobutylgaba (30 mg/kg s.c.) 1 h after surgery also completely
blocked the maintenance of hyperalgesia and allodynia, but its duration of action was much
shorter (3 h). The administration of morphine (1-6 mg/kg s.c.) 0.5 h before surgery
prevented the development of thermal hyperalgesia with a MED of 1 mg/kg. However, unlike
gabapentin and S-(+)-3-isobutylgaba, it had little effect on the development of tactile
allodynia. It is suggested that gabapentin and S-(+)-3-isobutylgaba may be effective in the
treatment of postoperative pain. Pain 1997 Sep;72(3):375-382 Gabapentin enhances the
antinociceptive effects of spinal morphine in the rat tail-flick test. Shimoyama M, Shimoyama N, Inturrisi CE, Elliott KJ Department of Pharmacology, Cornell
University Medical College, New York, NY 10021, USA. The antinociceptive effects of the combination of spinal morphine and gabapentin were
evaluated in the tail-flick test in rats. The intrathecal coadministration of a
subantinociceptive dose of morphine at 0.2 microgram and gabapentin at 300 micrograms
produced significant antinociception. Pretreatment with spinal gabapentin at 300
micrograms shifted the dose-response curve of spinal morphine to the left with a decrease
in morphine ED50 value from 1.06 micrograms to 0.34 microgram. The antinociceptive effects
produced by the combination of a subantinociceptive dose of morphine and gabapentin were
reversed by spinal naloxone at 30 micrograms but were not reversed by spinal bicuculline
at 0.3 microgram. Furthermore, the concurrent administration of spinal naloxone at 30
micrograms with the combination of morphine and gabapentin blocked antinociception, while
the concurrent administration of spinal bicuculline at 0.3 microgram failed to prevent
antinociception. These results indicate that the combination of spinal gabapentin and
morphine produces an enhancement of antinociception that appears to involve the spinal mu
opioid receptors. Furthermore, repeated administration of gabapentin for 3 days did not
affect the enhancing effect of gabapentin on the antinociceptive effect of morphine,
indicating that tolerance did not develop to gabapentin's ability to enhance morphine
antinociception. Clin J Pain 1997 Sep;13(3):251-255 The effect of gabapentin on
neuropathic pain. Rosenberg JM, Harrell C, Ristic H, Werner RA, de Rosayro AM Department of
Anesthesiology, University of Michigan Health System, Ann Arbor, USA. OBJECTIVE: To evaluate the effects of gabapentin on pain scores and opiate use. DESIGN: Retrospective review of patients charts who received gabapentin for at least 30
days. Data were collected concerning patients' diagnosis, current drug use, concurrent
drug use, gabapentin dose, pain scores, and patient-reported side effects. Patients were
divided into three groups based on their pain diagnosis; low back, neuropathic, and
myofascial pain. The neuropathic group was subdivided into postherpetic neuralgia,
diabetic neuropathy, sympathetically maintained pain, and phantom pain. SETTING: Two tertiary referral teaching hospitals in southeastern Michigan. RESULTS: A total of 122 charts were reviewed and included in this study. A significant
decrease in pain scores with gabapentin was seen in the neuropathic pain group (paired
t-test, p < .0001) but not in the low back pain group. Of the neuropathic pain group,
patients with postherpetic neuralgia had the greatest decrease in pain scores. Ten
patients showed a > 75% decrease in pain scores, of these: nine had a direct nerve
injury, and one had postherpetic neuralgia. Opiate use was unchanged in all groups.
Patients who were taking opiates had significantly less benefit with gabapentin use in
terms of pain score. Patient-reported side effects were similar to those reported in a
nonchronic pain population. CONCLUSION: Gabapentin may be a useful adjunct for treating neuropathic pain with a
minimum of side effects. Particular advantage may be gained with the use of this drug for
postherpetic neuralgia and direct peripheral nerve injuries. Ann Pharmacother 1997 Sep;31(9):1082-1083 Use of gabapentin in pain management.
Wetzel CH, Connelly JF School of Pharmacy, Campbell University, Buies Creek, NC, USA. There have been many proposed uses for gabapentin, including midscapular pain secondary
to radiation myelopathy, RSD, neuropathic pain, postherpetic neuralgia, and migraine
prophylaxis. However, the published reports consist of a small number of patients and
limited data. Limited data provided in published case reports do not allow adequate
evaluation of expected adverse effects or efficacy. It is unclear whether gabapentin is
more effective for a specific type of pain and how gabapentin may compare with placebo or
other therapeutic alternatives. Therefore, randomized, double-blind, placebo-controlled,
prospective studies are warranted to further elucidate gabapentin uses beyond what is
recommended by the Food and Drug Administration. Gabapentin should only be considered for
pain management after well-established therapies have failed to produce desired outcomes. Br J Pharmacol 1997 Aug;121(8):1513-1522 Gabapentin (neurontin) and
S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents.
Field MJ, Oles RJ, Lewis AS, McCleary S, Hughes J, Singh L Department of Biology,
Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site. 1. Gabapentin (neurontin) is a novel antiepileptic agent that binds to the alpha 2
delta subunit of voltage-dependent calcium channels. The only other compound known to
possess affinity for this recognition site is the (S)-(+)-enantiomer of 3-isobutylgaba.
However, the corresponding (R)-(-)-enantiomer is 10 fold weaker. The present study
evaluates the activity of gabapentin and the two enantiomers of 3-isobutylgaba in formalin
and carrageenan-induced inflammatory pain models. 2. In the rat formalin test, S-(+)-3-isobutylgaba (1-100 mg kg-1) and gabapentin
(10-300 mg kg-1) dose-dependently inhibited the late phase of the nociceptive response
with respective minimum effective doses (MED) of 10 and 30 mg kg-1, s.c. This
antihyperalgesic action of gabapentin was insensitive to naloxone (0.1-10.0 mg kg-1,
s.c.). In contrast, the R-(-)-enantiomer of 3-isobutylgaba (1-100 mg kg-1) produced a
modest inhibition of the late phase at the highest dose of 100 mg kg-1. However, none of
the compounds showed any effect during the early phase of the response. 3. The s.c. administration of either S-(+)-3-isobutylgaba (1-30 mg kg-1) or gabapentin
(10-100 mg kg-1), after the development of peak carrageenan-induced thermal hyperalgesia,
dose-dependently antagonized the maintenance of this response with MED of 3 and 30 mg
kg-1, respectively. Similar administration of the two compounds also blocked maintenance
of carrageenan-induced mechanical hyperalgesia with MED of 3 and 10 mg kg-1, respectively.
In contrast, R-(-)-3-isobutylgaba failed to show any effect in the two hyperalgesia
models. 4. The intrathecal administration of gabapentin dose-dependently (1-100
micrograms/animal) blocked carrageenan-induced mechanical hyperalgesia. In contrast,
administration of similar doses of gabapentin into the inflamed paw was ineffective at
blocking this response. 5. Unlike morphine, the repeated administration of gabapentin (100 mg kg-1 at start and
culminating to 400 mg kg-1) over 6 days did not lead to the induction of tolerance to its
antihyperalgesic action in the formalin test. Furthermore, the morphine tolerance did not
cross generalize to gabapentin. The s.c. administration of gabapentin (10-300 mg kg-1),
R-(-) (3-100 mg kg-1) or S-(+)-3-isobutylgaba (3-100 mg kg-1) failed to inhibit
gastrointestinal motility, as measured by the charcoal meal test in the rat. Moreover, the
three compounds (1-100 mg kg-1, s.c.) did not generalize to the morphine discriminative
stimulus. Gabapentin (30-300 mg kg-1) and S-(+)-isobutylgaba (1-100 mg kg-1) showed
sedative/ataxic properties only at the highest dose tested in the rota-rod apparatus. 6. Gabapentin (30-300 mg kg-1, s.c.) failed to show an antinociceptive action in
transient pain models. It is concluded that gabapentin represents a novel class of
antihyperalgesic agents. Ther Drug Monit 1997 Aug;19(4):394-396 Changes in body weight with chronic,
high-dose gabapentin therapy. DeToledo JC, Toledo C, DeCerce J, Ramsay RE Department of Neurology, University of
Miami, FL 33136, USA. The authors reviewed changes in body weight in 44 patients treated with Gabapentin
(GPN) for a period of 12 or more months. All patients had a seizure disorder and the dose
of GPN was increased aiming at complete seizure control or until side effects limited
further increase. Twenty-eight patients were receiving GPN dosages of > 3000 mg/day.
Observed changes in body weight were as follows 10 patients gained more than 10% of their
baseline weight, 15 patients gained 5% to 10% of baseline, 16 patients had no change, and
3 patients lost 5% to 10% of their initial weight. Weight increase started between the
second and the third months of GPN treatment in most patients and tended to stabilize
after 6 to 9 months of treatment, although the doses of GPN remained unchanged. Weight
gain occurred in patients taking GPN in combination with each of the major antiepileptic
drugs including Felbatol and also occurred with GPN monotherapy. Brain Inj 1997 Jul;11(7):537-540 Psychomotor agitation following
gabapentin use in brain injury. Childers MK, Holland D Department of Physical Medicine and Rehabilitation, University
of Missouri-Columbia, USA. Gabapentin, an anticonvulsant structurally related to gamma-aminobutyric acid (GABA)
was recently reported to be effective in pain associated with reflex sympathetic dystrophy
(RSD) and in pain associated with neuropathy. Yet, to our knowledge, the use of gabapentin
for neuropathic pain in the presence of cognitive impairment has not been reported. In
this report, we describe two patients (one with a traumatic brain injury, one with a
putative acquired brain injury) who presented to a neurorehabilitation unit complaining of
pain that was diagnosed as neurologically mediated. Within one week of receiving a daily
900 mg dose of gabapentin, both patients complained of heightened anxiety and
restlessness. Correspondingly, each reported a diminution of psychological symptoms within
48 hours of gabapentin cessation. These two cases suggest that gabapentin may cause
agitation in cognitive impaired patients. Physicians treating brain-injured patients and
prescribing gabapentin for neuropathic pain may wish to closely monitor patients for
similar signs of restlessness or anxiety. Ann Clin Psychiatry 1997 Jun;9(2):99-103 A pilot trial of adjunctive gabapentin
in the treatment of bipolar disorder. McElroy SL, Soutullo CA, Keck PE Jr, Kmetz GF Department of Psychiatry, University of
Cincinnati College of Medicine, Ohio 45267-0559, USA. Several antiepileptic drugs (AEDs) have documented efficacy in the manic phase of
bipolar disorder. To investigate the efficacy, tolerability, and safety of the new AED,
gabapentin, in mania, we treated nine consecutive outpatients with bipolar I or II
disorder by DSM-IV criteria who were experiencing hypomanic, manic, or mixed states
inadequately responsive to standard mood stabilizers with open-label, adjunctive
gabapentin. Response of manic symptoms was assessed monthly as none, minimal, moderate, or
marked. Of the nine patients, seven displayed a moderate or marked reduction in manic
symptoms by 1 month after addition of gabapentin, and an additional patient displayed
moderate improvement after 3 months. Of these eight patients, six displayed continued
antimanic responses for follow-up periods ranging from 1 to 7 months. Side effects were
most commonly neurological, mild, and transient. Adjunctive gabapentin may have antimanic
and mood-stabilizing effects in some patients with bipolar disorder and is generally well
tolerated. Controlled studies of gabapentin in bipolar disorder appear to be warranted. Epilepsy Res 1997 Jun;27(3):175-180 Neurochemical actions of gabapentin
in mouse brain. Leach JP, Sills GJ, Butler E, Forrest G, Thompson GG, Brodie MJ University Department
of Medicine and Therapeutics, Western Infirmary, Glasgow, UK. Gabapentin (GBP) is a recently licensed antiepileptic, drug whose mode of action
remains to be fully elucidated. The following studies were designed to investigate the
effects of GBP on several gamma-aminobutyric acid (GABA) related neurochemical parameters
in mouse brain. GBP (0-75 mg/kg) was administered by intraperitoneal injection either as a
single dose or twice daily for 8 days. Animals were sacrificed 4 h after the final
administration and their brains removed and analysed for concentrations of GABA, glutamate
and glutamine and the activities of GABA-transaminase (GABA-T) and glutamic acid
decarboxylase (GAD). Single dose GBP increased brain GABA-T activity and glutamine
concentration but was without effect on GAD activity or the concentrations of GABA and
glutamate. Following repeated treatment with GBP, brain GABA-T activity was consistently
decreased and there was also a decrease in brain glutamate concentration. Repeated drug
treatment was without effect on the activity of GAD or on the concentrations of GABA and
glutamine. These results suggest that GBP has effects on the GABAergic system which may
contribute to its antiepileptic and/or neuroprotective actions. Ann Neurol 1997 Jun;41(6):818-825 A double-blind controlled study of gabapentin and baclofen as treatment for acquired
nystagmus. Averbuch-Heller L, Tusa RJ, Fuhry L, Rottach KG, Ganser GL, Heide W, Buttner U, Leigh
RJ Department of Neurology, Veterans Affairs Medical Center, Cleveland, OH, USA. We conducted a double-blind crossover trial comparing gabapentin (up to 900 mg/day) to
baclofen (up to 30 mg/day) as therapy for acquired nystagmus in 21 patients. We measured
visual acuity and the nystagmus before, and at the end of, 2 weeks on each medication. For
a group of 15 patients with acquired pendular nystagmus (APN), visual acuity improved
significantly with gabapentin, but not with baclofen. Gabapentin significantly reduced APN
median eye speed in all three planes, but baclofen did so only in the vertical plane. In
10 patients with APN, the reduction of nystagmus with gabapentin was substantial and 8 of
these elected to continue taking the drug. In 6 patients with downbeat or torsional
downbeat nystagmus, changes in median slow-phase eye speed were less consistent with both
drugs, either increasing or decreasing, and being dependent on viewing conditions. Only 1
patient showed consistent reduction of median eye speed, and this was achieved by either
drug. Our findings suggest that gabapentin may be an effective treatment for many patients
with APN and that occasional patients with downbeat nystagmus will respond to gabapentin
or baclofen. Reg Anesth 1997 May;22(3):249-256 Effect of subarachnoid gabapentin on
tactile-evoked allodynia in a surgically induced neuropathic pain model in the rat.
Hwang JH, Yaksh TL Department of Anesthesiology, University of California, San Diego,
La Jolla 92093-0818, USA. BACKGROUND AND OBJECTIVES: Spinal gamma-aminobutyric acid (GABA) receptors have been
shown to modulate post-nerve injury-induced allodynia. This study sought to examine the
antiallodynic effects of a GABA analog gabapentin [1-(aminomethyl)cyclohexaneacetic acid],
given by subarachnoid injection in a rat neuropathic pain model. METHODS: The rats were
prepared with lumbar subarachnoid catheters, and allodynia was induced in rats by ligation
of the L5-6 nerve roots (Chung model). RESULTS: Spinal injection of gabapentin resulted in a dose-dependent (10-1,000 microg)
antagonism of the allodynia at doses that had no detectable effect on motor function.
Subarachnoid injection of either the GABA A antagonist bicuculline (0.3 microg), or the
GABA B antagonist CGP 35348 (30 microg) 5 minutes before or 60 minutes after injection of
GABA receptor agonist did not reverse the antiallodynic effects produced by gabapentin. CONCLUSIONS: Gabapentin shows antiallodynic effect, but its mechanism is not known. The
failure to reverse this effect by GABA A or B antagonists at doses that reverse the
effects of the respective agonists suggests that gabapentin is involved in the modulation
of spinal systems by mechanisms that do not involve either a GABA A or a GABA B site. Arch Phys Med Rehabil 1997 May;78(5):521-524 Gabapentin for relief of upper motor
neuron symptoms in multiple sclerosis. Mueller ME, Gruenthal M, Olson WL, Olson WH Department of Internal Medicine, University
of Louisville School of Medicine, KY, USA. OBJECTIVE: To examine the efficacy of gabapentin in the treatment of spasticity and
painful muscle spasms in patients with multiple sclerosis. DESIGN: Double-blind,
placebo-controlled crossover study. SETTING: Free-standing, 93-bed, university-affiliated
rehabilitation hospital. PARTICIPANTS: There were 15 patients between the ages of 18 and
50 who had laboratory-supported definite multiple sclerosis with spasticity and leg cramps
severe enough to interfere with daily activities, including sleep. INTERVENTION: The
patients received the placebo or 400mg gabapentin orally three times a day for 48 hours
with an 11-day washout period. If the patients were on currently accepted modes of
therapy, including oral baclofen, their current medication was not changed. MAIN OUTCOME
MEASURES: The outcome measures were Visual Faces Scale rating, Kurtzke Disability Scale,
quantitative surface electromyography, Ashworth Scale, presence or absence of clonus in
response to rapid ankle dorsiflexion and wrist extension, presence or absence of reflex
withdrawal in response to nailbed pressure to the first finger, and assessment of Babinski
response. RESULTS: Statistically significant improvements for the gabapentin treated
patients were found in the Ashworth Scale, Visual Faces Scale, and Kurtzke Disability
Scale. CONCLUSIONS: At a dose of 400mg orally three times a day, gabapentin may be of value in
the treatment of the spasticity and painful muscle cramping experienced by patients with
multiple sclerosis. Eur J Pharmacol 1997 Apr 18;324(2-3):153-160 The effect of novel anti-epileptic drugs
in rat experimental models of acute and chronic pain. Hunter JC, Gogas KR, Hedley LR, Jacobson LO, Kassotakis L, Thompson J, Fontana DJ
Department of Analgesia, Institute of Pharmacology, Roche Bioscience, Palo Alto, CA 94304,
USA. john.hunter@roche.com The novel anti-epileptic drugs lamotrigine, felbamate and gabapentin were compared in
rat experimental models of acute (tail flick) and chronic pain: the chronic constriction
injury and spinal nerve ligation models. Lamotrigine (10-100 mg/kg, s.c.), felbamate
(150-600 mg/kg, i.p.) and gabapentin (30-300 mg/kg, i.p.) each reversed cold allodynia
(chronic constriction injury model) with ED50 values of 28, 241 and 103 mg/kg,
respectively, 1 h post-dose. However, only gabapentin reversed tactile allodynia (spinal
nerve ligation model) with an ED50 of 34 mg/kg (i.p.). The established anti-epileptic
drugs, carbamazepine (1-30 mg/kg, i.p.) and phenytoin (1-100 mg/kg, s.c.), were
ineffective in both models. The anti-allodynic effect of the newer anti-epileptic drugs
was observed at doses that were either ineffective or produced only a negligible effect on
acute nociceptive function and/or locomotor activity. In conclusion, the data suggest that the newer anti-epileptic drugs appear to have the
potential to be effective alternatives to either carbamazepine or phenytoin in the
treatment of neuropathic pain. However, only gabapentin ameliorated both cold and touch
hyperesthesias. Clin Neuropharmacol 1997 Apr;20(2):148-151 Treatment of restless legs syndrome with
gabapentin. Adler CH Parkinson's Disease and Movement Disorders Center, Department of Neurology,
Mayo Clinic Scottsdale, AZ 85259, USA. Gabapentin is a well tolerated anticonvulsant, structurally related to
gamma-aminobutyric acid, with an unknown mechanism of action. Restless legs syndrome (RLS)
is a disorder characterized by sensory and motor symptoms in the legs that is best treated
with dopaminergic drugs and opiates. In this open-label study, eight patients with RLS
were treated with gabapentin. Four of the eight had a beneficial response, three with
almost complete resolution of symptoms for up to 6 months. For a disorder that is often
difficult to treat, these results are encouraging, and they suggest that a
placebo-controlled trial is warranted. Neuroreport 1997 Feb 10;8(3):587-590 Gabapentin, ineffective in normal rats,
markedly reduces C-fibre evoked responses after inflammation. Stanfa LC, Singh L, Williams RG, Dickenson AH Department of Pharmacology, University
College London, UK. Gabapentin (Neurontin) is a novel anticonvulsant with an as yet unknown mechanism of
action. This electrophysiological study investigated the potential antinociceptive actions
of systemically administered gabapentin in normal animals and after inflammation induced
by the injection of carrageenan. Gabapentin facilitated the noxious evoked responses of
dorsal horn neurones recorded in normal animals. In complete contrast, gabapentin strongly
and dose-dependently inhibited the C-fibre evoked response and post-discharge, but not the
A beta-fibre evoked response, of neurones recorded in animals 3 h after the injection of
carrageenan. This unique and selective profile of gabapentin may provide a novel treatment
for clinical inflammatory pain states. Neurosci Lett 1997 Jan 24;222(1):65-67 Spinal gabapentin is antinociceptive
in the rat formalin test. Shimoyama N, Shimoyama M, Davis AM, Inturrisi CE, Elliott KJ Department of
Pharmacology, Cornell University Medical College, New York 10021, USA. Gabapentin is a novel anticonvulsant that may be of value for the relief of clinical
pain. To determine whether gabapentin is antinociceptive after spinal administration, the
drug was given via an intrathecal catheter in doses from 6 to 200 micrograms/rat 10 min
prior to intraplantar formalin. Five percent formalin injected subcutaneously in the right
hind paw produced a biphasic reaction consisting of flinching and licking behaviors (phase
1, 0-10 min; phase 2, 10-60 min). Gabapentin dose-dependently reduced the numbers of
flinches and the duration of licking during phase 2 of the formalin test. The highest dose
of gabapentin (200 micrograms/rat) did not affect the tail-flick response. These results
demonstrate that spinal gabapentin is antinociceptive in the formalin test. Am J Med 1997 Jan;102(1):60-66 Gabapentin for parkinsonism: a
double-blind, placebo-controlled, crossover trial. Olson WL, Gruenthal M, Mueller ME, Olson WH Department of Neurology, University of
Louisville, Kentucky 40292, USA. PURPOSE: Gabapentin is a recently available anticonvulsant whose mechanism of action
remains unknown. We suspected efficacy from serendipitous observations of gabapentin in
patients with parkinsonism. This led us to a double-blind, placebo-controlled, crossover
trial. PATIENTS AND METHODS: We administered gabapentin in a placebo-controlled,
double-blind, crossover trial to 19 subjects with advanced parkinsonism. We measured the
effect of placebo and gabapentin on subjects' symptoms with the Unified Parkinson's
Disease Rating Scale, the Webster Scale, and the Hoehn and Yahr Scale. We assessed tremor
with surface-recorded electromyography. RESULTS: Total Unified Parkinson's Disease Rating
Scale improved with gabapentin compared with placebo (P = 0.0005). Likewise, activities of
daily living and examination subscore of the Unified Parkinson's Disease Rating Scale
improved with gabapentin compared with placebo but did not achieve statistical
significance. Webster Scale showed improvement but neither Hoehn and Yahr Scale nor
Webster Scale changes reached statistical significance. Tremor as measured by the Unified
Parkinson's Disease Rating Scale improved with gabapentin but the use of the root mean
square of the rectified electromyography as a measure of tremor activity was not
statistically significant. CONCLUSIONS: This study demonstrates that gabapentin improves rigidity, bradykinesia,
and tremor of parkinsonism including both Parkinson's disease and Parkinson's syndrome.
The rigidity and bradykinesia of parkinsonism improve on the drug even when the effects of
gabapentin on tremor are discounted. Arch Phys Med Rehabil 1997 Jan;78(1):98-105 Reflex sympathetic dystrophy treated with
gabapentin. Mellick GA, Mellick LB American Pain Specialists, Inc., Elyria, OH 44035, USA. The use of the recently released anticonvulsant, gabapentin (Neurontin), in the
treatment of severe and refractory reflex sympathetic dystrophy (RSD) pain in six patients
ranging in age from 42 to 68 years is reported. Satisfactory pain relief obtained in all
six patients suggests that this medication is an effective treatment for RSD pain. In
addition to pain control, early evidence of disease reversal in these patients is
suggested. Patient 6 is the first documented case of successful treatment and cure of the
RSD pain syndrome using gabapentin alone. Specifically, reduced hyperpathia, allodynia,
hyperalgesia, and early reversal of skin and soft tissue manifestations were noted.
Gabapentin was chosen because it has properties similar to other anticonvulsant drugs and
because previous studies have shown that it is well tolerated and appears to have a benign
efficacy-to-toxicity ratio. It was considered an acceptable and compassionate therapeutic
choice because previous medical and surgical approaches had been ineffective for these
patients, who represent the first case series documenting the use of gabapentin for pain
management. Presently, the mechanism of pain relief in these patients is unknown. In this
article, the pathophysiology of RSD is discussed, and a mechanism by which gabapentin
provides pain relief is proposed. In view of e
