1999 Neurontin Research for Off-Label Purposes


Updated 7/27/01

Sea Critters

J Affect Disord 1999 Oct;55(2-3):237-40

Open maintenance treatment of bipolar disorder spectrum patients who responded to gabapentin augmentation in the acute phase of treatment.

Schaffer CB, Schaffer LC Department of Psychiatry, UC Davis School of Medicine, Sacramento, CA 95816, USA.

This report describes the results of maintenance treatment with gabapentin in 18 previously refractory Bipolar Disorder patients who initially responded to augmentation with gabapentin during the acute phase of their therapy. Seven of the original 18 patients (39%) have continued to experience benefit from maintenance gabapentin treatment. Only three patients had to discontinue the gabapentin because of side effects. None of the 18 patients experienced an obvious significant adverse drug-drug interaction. Five of the patients discontinued gabapentin because of diminished clinical efficacy after a significant period of positive therapeutic effect. The results of this small open study suggest that gabapentin may be effective as an augmenting agent in the maintenance phase of treatment of some bipolar spectrum patients.

Ther Drug Monit 1999 Dec;21(6):615-7

A case of sustained massive gabapentin overdose without serious side effects. Verma A, St Clair EW, Radtke RA Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

Gabapentin is an antiepileptic agent that is indicated for use as adjunctive therapy for partial seizures. It has a relatively benign side effect profile, but little data exists on massive overdoses with this agent. The authors present a case of a patient who received a massive overdose of this agent but suffered no clinically significant toxicity.

Pharmacopsychiatry 1999 Nov;32(6):255-7

Gabapentin leads to remission of somatoform pain disorder with major depression. Maurer I, Volz HP, Sauer H Department of Psychiatry, Friedrich-Schiller-Universitat Jena, Germany. maurer@landgraf.med.uni-jena.de

Gabapentin, a novel antiepileptic drug, is effective in the treatment of partial seizures with and without secondary generalization. Evidence suggests that it may have mood-stabilizing and possibly antidepressant properties in bipolar depression. We report on a 48-year-old woman who had recurrent major depressive disorder. Following inguinal herniorrhaphy, she developed severe stabbing pain in the lower abdomen and inguinal area that progressed to constant pain in her whole body. She was depressive, hopeless, and had given up her social activities. A diagnosis of major depressive disorder and somatoform pain disorder was made. Antidepressants and carbamazepine were ineffective, and she had attempted suicide. Gabapentin resulted in remission of both the pain and the depressive mood at a dose of 1.800 mg/day

. Ann Clin Psychiatry 1999 Dec;11(4):217-22

Gabapentin as an adjunct to standard mood stabilizers in outpatients with mixed bipolar symptomatology.

Sokolski KN, Green C, Maris DE, DeMet EM Mental Health Care Group, Veterans Affairs Medical Center, Long Beach, California 90822, USA.

Gabapentin is a new adjunctive medication to antiseizure therapies. Anecdotal evidence suggests that it may also help to alleviate mood symptoms in patients with bipolar illness. An open-label study examined the effects of adjunctive gabapentin in bipolar patients with mixed symptoms who had previously demonstrated only partial treatment responses. Mood ratings and side-effect profiles were followed weekly in 10 patients for 1 month. Decreases in Hamilton depression (P < 0.05) and Bech mania ratings (P > 0.01) were evident in the first week of treatment and were sustained. Potent early improvements were noted in early, middle, and late insomnia. The results suggest that gabapentin may be of benefit to bipolar patients who only partially respond to other mood stabilizers. A favorable side-effect profile and rapid action make this drug an attractive choice as an adjunctive therapy.

J Am Dent Assoc 1999 Oct;130(10):1467-9

Antidepressant-induced bruxism successfully treated with gabapentin. Brown ES, Hong SC Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas 75235-9101, USA.

BACKGROUND: Symptoms consistent with bruxism are a common chief complaint in dental practice. The authors describe a case of bruxism likely induced by the antidepressant venlafaxine and successfully treated with gabapentin. CASE DESCRIPTION: A case of bruxism, anxiety, insomnia and tremor is reported in a man with bipolar disorder that developed a few days after he initiated venlafaxine therapy for depression. The patient's psychiatrist prescribed gabapentin for anxiety symptoms, and shortly thereafter the man experienced a complete resolution of the bruxism. CLINICAL IMPLICATIONS: On the basis of this case and the available literature, the authors conclude that bruxism secondary to antidepressant therapy may be common. Thus, dentists should inquire about the use of these medications in patients who have bruxism. Gabapentin may offer promise in the treatment of this condition.

Am J Health Syst Pharm 1999 Oct 1;56(19):1939-44

Gabapentin and lamotrigine in bipolar disorder.

Botts SR, Raskind J College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY 11439, USA. Botts@lij.edu

The utility of gabapentin and lamotrigine for the treatment of bipolar disorder is reviewed. Bipolar disorder is characterized by extreme mood fluctuations, including mania, hypomania, depression, and mixed episodes. Extrapolation of postulated mechanisms of anticonvulsant activity in bipolar disorder has led to the use of the newer anticonvulsants gabapentin and lamotrigine for therapy. Both agents appear promising on the basis of limited (often anecdotal) evidence. They may prove effective in patients with difficult cases of bipolar disorder, such as patients with rapid cycling, mixed episodes, and illness refractory to other treatments. Lamotrigine may offer a much-needed treatment alternative for bipolar depression and could be found effective for acute mania, but the need for slow dosage adjustment and the risk of rash may limit overall clinical utility. Gabapentin may offer significant advantages for acute mania: The dosage can be adjusted rapidly, adverse effects are generally minimal, the therapeutic index is high, there is no required laboratory monitoring, and there is minimal potential for interactions with other psychotropics. Until the results of randomized controlled trials are known, however, these two agents should be reserved for patients with bipolar disorder unresponsive to traditional therapies and for patients who cannot tolerate traditional agents. Preliminary evidence indicates that gabapentin and lamotrigine may be useful for the treatment of bipolar disorder.

Eur Neuropsychopharmacol 1999 Aug;9 Suppl 4:S113-7

Lamotrigine in the treatment of bipolar depression.

Bowden CL, Mitchell P, Suppes T Department of Psychiatry, University of Texas, Health Science Center at San Antonio, 78284-7792, USA.

Several case reports and open studies have reported the efficacy of lamotrigine in bipolar depression. A randomised placebo-controlled 7-week study comparing two doses of lamotrigine with placebo in 195 patients with moderate to severe bipolar depression has now been completed. Lamotrigine was superior to placebo after 3 weeks as assessed by changes in the Montgomery-Asberg Depression Rating Scale (MADRS). A response, defined as more than 50% improvement on the MADRS occurred in 56 and 48% of the lamotrigine 200 and 50 mg/day groups, respectively, compared with 29% for placebo (P<0.05). There was no evidence that lamotrigine destabilised mood or precipitated mania. Tolerability was good and there were no cases of serious rashes. Preliminary results from an ongoing study also indicate that lamotrigine is more effective than gabapentin in bipolar depression. In conclusion, lamotrigine is effective in alleviating bipolar depression, without causing mood destabilisation. Slow dosage escalation yields good tolerability.

Semin Pediatr Neurol 1999 Sep;6(3):182-8; discussion 189

An 8-year-old girl with unilateral facial and ear pain and isolated frontal headaches.

Gay CT Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, USA.

An 8 1/2-year-old with chronic but fluctuating unilateral facial pain, earache, frontal headache and facial swelling is presented. Her journey through the health care system provides an instructional lesson for all who deal with patients with unusual or difficult to recognize conditions.

J Affect Disord 1999 Sep;55(1):73-7

Gabapentin as an adjunctive treatment in bipolar disorder.

Young LT, Robb JC, Hasey GM, MacQueen GM, Patelis Siotis I, Marriott M, Joffe RT Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada. youngt@fhs.mcmaster.ca

OBJECTIVE: To evaluate the efficacy of gabapentin as an adjunctive treatment for bipolar disorder in both depressed and manic phases. METHOD: Thirty seven patients with bipolar type I or II with or without a rapid cycling course were openly treated with gabapentin added to current treatment for up to six months. Mood symptoms were rated weekly for 12 weeks then monthly for 3 months utilizing the HamD and YMS. RESULTS: Participants experienced a significant reduction in both depressive and manic symptoms. CONCLUSIONS: These findings are consistent with others in establishing the efficacy of gabapentin in both phases of bipolar disorder. LIMITATIONS: Small sample size and the use of an open uncontrolled design limit interpretation of results.

Can Fam Physician 1999 Sep;45:2109-12

Using gabapentin to treat neuropathic pain.

Hays H, Woodroffe MA

OBJECTIVE: To review use of gabapentin as an adjuvant agent to treat neuropathic pain. QUALITY OF EVIDENCE: MEDLINE was searched from 1995 to October 1998 for reports. There were approximately 20 citations. Additional articles from Pain and other medical journals were reviewed. No double-blind studies have examined gabapentin and its use as an analgesic adjuvant agent. MAIN MESSAGE: Gabapentin is an anticonvulsant medication used recently as an effective adjuvant agent for treating neuropathic pain. It is a structural analogue of gamma-aminobutyric acid (GABA), but its receptor and biochemical function remain unknown. Gabapentin has desirable pharmacokinetic properties and acceptable side effects, which simplify its use. There are very few interactions between gabapentin and other medications, and gabapentin is well tolerated. CONCLUSION: Gabapentin could be an effective adjuvant agent for many neuropathic pain states.

Arch Intern Med 1999 Sep 13;159(16):1931-7

Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain.

Morello CM, Leckband SG, Stoner CP, Moorhouse DF, Sahagian GA Veterans Affairs San Diego Healthcare System, Calif 92161, USA.

BACKGROUND: Reports of gabapentin use in diabetic peripheral neuropathy pain stimulate a need for controlled trials to determine its comparative efficacy to the therapeutic standard of amitriptyline hydrochloride. OBJECTIVE: To determine the efficacy of gabapentin compared with amitriptyline in treating diabetic peripheral neuropathy pain. DESIGN: Prospective, randomized, double-blind, double-dummy, crossover study. SETTING: Veterans Affairs San Diego Healthcare System, Ambulatory Care Clinic. PATIENTS: Twenty-eight veterans were referred by their primary care providers. Two patients withdrew before randomization because of no neuropathic pain after washout; a third withdrew for unexpected surgery that required analgesics. Three patients withdrew because of adverse effects and 1 for protocol violation. INTERVENTIONS: Patients with stable glycemic control and neuropathic pain randomized to 6 weeks of therapy with gabapentin, 900 to 1800 mg/d, or amitriptyline hydrochloride, 25 to 75 mg/d, with a 1-week washout before crossover. MAIN OUTCOME MEASURES: Pain relief measured by pain scale with verbal descriptors and global pain score assessment at treatment end. RESULTS: Participants and investigators were blinded throughout. Mean dosages were of gabapentin, 1565 mg/d, and of amitriptyline hydrochloride, 59 mg/d. Sixty-five percent of patients reached maximum dose with gabapentin and 54% with amitriptyline. Mean score diary analysis showed pain relief with gabapentin and amitriptyline was not significantly different (P = .26). Global data were obtained from 21 of 25 enrolled patients who completed the study. Moderate or greater pain relief was experienced in 11 (52%) of 21 patients with gabapentin and 14 (67%) of 21 patients with amitriptyline. There were no significant period or carry-over effects (P = .35). CONCLUSIONS: Although both drugs provide pain relief, mean pain score and global pain score data indicate no significant difference between gabapentin and amitriptyline. Gabapentin may be an alternative for treating diabetic peripheral neuropathy pain, yet does not appear to offer considerable advantage over amitriptyline and is more expensive. Larger trials are necessary to define gabapentin's place in treating diabetic peripheral neuropathy pain.

Epilepsia 1999 Sep;40(9):1279-85

Differential cognitive effects of carbamazepine and gabapentin.

Meador KJ, Loring DW, Ray PG, Murro AM, King DW, Nichols ME, Deer EM, Goff WT Department of Neurology, Medical College of Georgia, Augusta 30912, USA. KMEADOR@NEURO.MCG.EDU

PURPOSE: The cognitive effects of the newer antiepileptic drugs (AEDs) compared with the older standard AEDs are uncertain. METHODS: We directly compared the cognitive effects of carbamazepine (CBZ) and gabapentin (GBP) in 35 healthy subjects by using a double-blind, randomized crossover design with two 5-week treatment periods. During each treatment condition, subjects received either GBP, 2,400 mg/day, or CBZ (mean, 731 mg/day) adjusted to a dose to achieve midrange standard therapeutic blood levels (mean, 8.3 microg/ml). Subjects were tested at the end of each AED treatment period and in four drug-free conditions [two pretreatment baselines and two post-treatment washout periods (1 month after each AED)]. The neuropsychological test battery included 17 measures yielding 31 total variables. RESULTS: Direct comparison of the two AEDs revealed significantly better performance on eight variables for GBP, but none for CBZ. Comparison of CBZ and GBP to the nondrug average revealed significant statistical differences for 15 (48%) of 31 the variables. Pairwise follow-up analyses of the 15 variables revealed significantly better performance for nondrug average on 13 variables compared with CBZ, and on four compared with GBP. GBP was better than nondrug average on one variable. CONCLUSIONS: Although both CBZ and GBP produced some effects, GBP produced significantly fewer untoward cognitive effects compared with CBZ at the dosages used in this study.

J Affect Disord 1999 Aug;54(3):315-7

Gabapentin as a promising treatment for antipsychotic-induced movement disorders in schizoaffective and bipolar patients.

Hardoy MC, Hardoy MJ, Carta MG, Cabras PL Institute of Psychiatry, University of Cagliari, Italy. ugolini@tin.it

Improvement of antipsychotic-induced blepharospasm and involuntary oral-mandibulo movements was observed with the use of the anticonvulsant drug gabapentin among 14 of 16 affectively ill patients who had been exposed to maintenance neuroleptics of the conventional type. In many cases, the movement disorders of these patients had not responded to more standard measures such as clozapine. This finding permits a potential strategy for patients with treatment-emergent tardive dyskinesia, a well-known complication of extended conventional neuroleptic use. Gabapentin, whose mood stabilizing properties have been reported in several clinical reports, represents a more natural treatment in the setting of bipolar spectrum disorders.

J Clin Psychopharmacol 1999 Aug;19(4):341-8

Treatment of social phobia with gabapentin: a placebo-controlled study.

Pande AC, Davidson JR, Jefferson JW, Janney CA, Katzelnick DJ, Weisler RH, Greist JH, Sutherland SM Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. atul.pande@wl.com

A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of social phobia. Sixty-nine patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 900 and 3,600 mg daily in three divided doses) or placebo for 14 weeks. A significant reduction (p < 0.05) in the symptoms of social phobia was observed among patients on gabapentin compared with those on placebo as evaluated by clinician- and patient-rated scales. Results were similar for the intent-to-treat and week-2 completer populations. Adverse events were consistent with the known side effect profile of gabapentin. Dizziness (p = 0.05), dry mouth (p = 0.05), somnolence, nausea, flatulence, and decreased libido occurred at a higher frequency among patients receiving gabapentin than among those receiving placebo. No serious adverse events or deaths were reported. On the basis of these limited data, it seems that gabapentin offers a favorable risk-benefit ratio for the treatment of patients with social phobia. Further studies are required to confirm this effect and to determine whether a dose-response relationship exists.

PMID: 10440462, UI: 99367074

Epilepsia 1999 Aug;40(8):1129-34

A beneficial effect on mood in partial epilepsy patients treated with gabapentin.

Harden CL, Lazar LM, Pick LH, Nikolov B, Goldstein MA, Carson D, Ravdin LD, Kocsis JH, Labar DR Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.

PURPOSE: Antiepileptic drugs (AEDs) are frequently used for their beneficial psychoactive effects on affective disorders. We sought to demonstrate a psychoactive effect of gabapentin (GBP) when used as add-on AED therapy. METHODS: Forty adult patients with partial epilepsy were studied in a prospective, non-randomized fashion with interviewer-rated and self-rated scales of mood and anxiety: the Cornell Dysthymia Rating Scale (CDRS), Beck Depression Inventory (BDI), and Hamilton Depression (Ham-D) and Anxiety (Ham-A) Scales. After completion of baseline mood and anxiety scales (time 1), 20 of the 40 patients were prescribed add-on GBP (treated group). The remaining 20 patients served as a control group. Both groups were similar in age and sex distribution. Follow-up mood and anxiety scales were performed in all patients approximately 3 months later (time 2). The average GBP dose at time 2 was 1,615 mg/day. All patients were taking stable doses of one to four AEDs at baseline and throughout the study. Seizure frequency was monitored throughout. Statistical significance was assessed by analysis of variance (ANOVA) by using a two-factor repeated-measures model. RESULTS: The GBP-treated group had a significant decrease in CDRS score over time compared with the control group (p = 0.04). No significant differences between the control and the treated groups were found for any of the remaining mood scales (BDI, p = 0.58; Ham-D, p = 0.59; Ham-A, p = 0.93). There was no significant difference or change in seizure frequency between groups. CONCLUSIONS: GBP treatment is associated with mood improvement as measured by the CDRS. This improvement was not accounted for by seizure improvement. PMID: 10448827, UI: 99376057

Drugs Exp Clin Res 1999;25(4):185-91

Low dose gabapentin for shoulder-hand syndrome induced by phenobarbital: a three-month study.

Rovetta G, Baratto L, Monteforte P Faculty of Rheumatology, University of Genoa, Rheumatological Center, Bruzzone Institute USL 3, Italy.

Both the pathogenetic interpretation and treatment of phenobarbital-induced rheumatism are uncertain. The reflex sympathetic dystrophy syndrome which complicates antiepileptic drug therapy is a problem for rheumatologists. The aim of our study was to test the effect of gabapentin as an additional therapy in patients suffering from phenobarbital-induced shoulder-hand syndrome when these patients were treated with gabapentin instead of receiving phenobarbital only. After a 3-month observation period, the pain and the movement range from the shoulder to the wrist and to the hand improved more than in the control group using acetaminophen. Further studies are required to confirm this observation. PMID: 10442276, UI: 99370864

Ann Clin Psychiatry 1999 Jun;11(2):61-6

The use of primidone in the treatment of refractory bipolar disorder.

Schaffer LC, Schaffer CB, Caretto J Sutter Community Hospitals, Sacramento, California, USA.

Four anticonvulsant medications (carbamazepine, valproate, gabapentin and lamotrigine) have received attention in the psychiatric literature as efficacious treatment for bipolar disorder, either as monotherapy or as adjunctive agents. Although two earlier reports in 1993 suggested that primidone may also be helpful for bipolar disorder, this older anticonvulsant has not been evaluated in any subsequent studies to confirm these earlier findings. In the present prospective open study, 26 patients with refractory bipolar disorder were treated with primidone as an adjunctive therapy. Eight (31%) patients experienced a persistent positive therapeutic effect. Five (19%) patients were considered partial or temporary responders to primidone. The remaining 13 patients (50%) were considered treatment failures. Although a 31% response rate is considered modest in most psychotropic medication studies, the authors believe that this success rate is significant in this refractory patient population and should provide impetus for future more scientific studies to confirm the preliminary findings of this open trial. PMID: 10440522, UI: 99367134

Anesth Analg 1999 Aug;89(2):434-9

The effect of intrathecal gabapentin on pain behavior and hemodynamics on the formalin test in the rat.

Yoon MH, Yaksh TL Department of Anesthesiology, University of California, San Diego 92093-0818, USA.

In this study, we examined the effect of intrathecal (i.t.) gabapentin, administered before and after the injection of formalin into the rat hindpaw, on pain behavior and hemodynamics. Formalin evoked a biphasic flinching behavior and hypertension. I.t. gabapentin administered 10 min before formalin produced a dose-dependent reduction of the Phase 2, but not Phase 1, flinching and cardiovascular response. In contrast, i.t. gabapentin administered 9 min after formalin had no effect on either phase of flinching. I.t. D-serine (100 micrograms) administered 10 min before i.t. galapentin reversed the Phase 2 effect of gabapentin. I.t. gabapentin did not affect the thermal escape latency or the baseline cardiovascular measures even at the largest dose (300 micrograms). These results indicate that the spinal effect of gabapentin reduces the somatosympathetic reflex and somatosensory response to tissue injury without an accompanying effect on acute nociception or resting sympathetic outflow. Implications: After tissue injury, there is an enhanced pain behavior and cardiovascular response, representing a facilitated state of spinal processing. Spinally delivered gabapentin had no evident effect on resting heart rate or blood pressure, but it attenuated the enhanced pain behavior and cardiovascular response otherwise produced by injury. PMID: 10439761, UI: 99368634

South Med J 1999 Jul;92(7):642-9

Treatment of chronic pain with antiepileptic drugs: a new era.

Hansen HC Department of Anesthesia and Pain Medicine, Davis Medical Center, Statesville, NC, USA.

BACKGROUND: Shortcomings of traditional pain relief agents have led physicians to investigate other alternatives, such as antiepileptic drugs. Safe, effective, nonhabituating agents are currently available to enhance pain treatment strategies. METHODS: In this article, various pharmacologic options and their mechanisms of action are reviewed briefly, with a focus on treatment of chronic pain with antiepileptic drugs (AEDs). RESULTS: Antiepileptic drugs have been widely studied and prescribed for the relief of acute and chronic pain. Similarities in the neurophysiology of pain and epilepsy suggest that AEDs may be a suitable adjunct in the management of chronic pain. Of the newer AEDs, gabapentin shows the greatest potential and appears to be well tolerated by patients. CONCLUSIONS: Treatment of chronic pain remains a challenge for physicians and patients. Further research is required to identify the role of various agents and their effect on patient return to function and quality of life. Publication Types: Review Review, tutorial PMID: 10414471, UI: 99341421

Arch Neurol 1999 Jul;56(7):807-8

A new twist for stopping the shakes? Revisiting GABAergic therapy for essential tremor.

Louis ED Department of Neurology and the Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Aside from physiological tremor, essential tremor (ET) is by far the most common cause of tremor in humans, affecting large numbers of individuals in every human population. The crude prevalence of ET has been conservatively estimated to be between 0.4% and 3.9%, although some estimates of the prevalence of ET among the elderly are higher than 20%. Essential tremor is the most prevalent adult-onset movement disorder, and is also regarded as one of the most common neurological disorders of adults, with a prevalence that is similar to or greater than that of stroke, Alzheimer disease, migraine headache, and lumbosacral pain syndromes. Essential tremor is as much as 20 times more prevalent than Parkinson disease. Publication Types: Review Review, tutorial PMID: 10404981, UI: 99331867

Eur Neurol 1999 Jul;42(1):49-51

Gabapentin as Treatment for Hemifacial Spasm.

Bandini F, Mazzella L Department of Neurological Sciences and Neurorehabilitation, University of Genoa, Italy.

Hemifacial spasm, a life-long condition characterized by involuntary unilateral contractions of the facial muscles, is a disabling disorder often resulting in patient irritation and social embarassment. Its probable etiology is neurovascular compression of the facial nerve at its root exit zone. The current medical treatment consists of either baclofen or anticonvulsant drugs, with limitation due to side effects or low efficacy. In recent years botulinum toxin injection and microvascular decompression of the facial nerve have been shown to be highly successful. However, both procedures share some complications and require special techniques. We present 5 patients affected by hemifacial spasm who responded well to the novel anticonvulsant drug gabapentin. Gabapentin was administered at a dose ranging from 900 to 1,600 mg daily, with rapid and clear improvement of spasms and absence of any remarkable adverse effects. Our findings suggest that gabapentin may be an effective treatment for patients with hemifacial spasm with a very good ratio of therapeutic effects to side effects when compared with other drugs currently used. PMID: 10394048

J Pain Symptom Manage 1999 Jun;17(6):441-5

Gabapentin as an adjuvant to opioid analgesia for neuropathic cancer pain.

Caraceni A, Zecca E, Martini C, De Conno F Pain Therapy and Palliative Care Division, National Cancer Institute of Milan, Italy.

Gabapentin was administered as an "add on" therapy to 22 patients with neuropathic cancer pain only partially responsive to opioid therapy. Global pain, burning pain, shooting pain episodes, and allodynia were assessed separately. Gabapentin was given for at least a week and efficacy was assessed after 7 to 14 days of therapy. Global pain score decreased from a mean (+/- SD) of 6.4 (+/- 1.5) to 3.2 (+/- 1.3) (95% confidence interval of the baseline minus final score differences [95% CI] = 1.0-2.4). Burning pain intensity decreased from a mean (+/- SD) of 5.1 (+/- 3.6) to 2.0 (+/- 2.3) (95% CI = 1.5-3.8), and episodes of shooting pain decreased in frequency from 7.2 (+/- 3.7) to 2.2 (+/- 2.2) daily episodes (95% CI = 1.8-4.3). Allodynia was found in 9 patients and disappeared in 7 during gabapentin administration. Twenty patients judged the new drug efficacious in relieving their symptoms. The potential role of gabapentin as an adjuvant to opioid analgesia in cancer pain is discussed. Publication Types: Clinical trial PMID: 10388250, UI: 99314305

Curr Opin Ophthalmol 1998 Oct;9(5):32-8

Nystagmus.

Gottlob I Department of Strabismus and Neuro-Ophthalmology, Kantonsspital St. Gallen, Switzerland.

This article reviews some of the past year's important papers, with emphasis on early onset and acquired neurological nystagmus. Advances in understanding the mechanisms of suppression of oscillopsia, the evolution of nystagmus, and the treatment of periodic alternating nystagmus and of nystagmus in albinism have been made in early-onset nystagmus. Successful pharmacological treatment for acquired neurological nystagmus has been demonstrated with the gamma aminobutyric acid agonist gabapentin and with memantine, a glutamate antagonist. Publication Types: Review Review, tutorial PMID: 10387479, UI: 99260054

Epilepsia 1999 May;40(5):590-600

New antiepileptic drugs: comparison of key clinical trials.

Cramer JA, Fisher R, Ben-Menachem E, French J, Mattson RH Yale University School of Medicine, New Haven, Connecticut, USA. Joyce.Cramer@Yale.edu

PURPOSE: Data accrued from clinical trials of five new antiepileptic drugs (AEDs) are compared for efficacy in reducing seizures and self-reported adverse events as a basis of selection among new AEDs. Drawbacks to use of these data also are demonstrated. METHODS: A review of double-blind, placebo-controlled clinical trials of a new AED or placebo added to a standard AED provided data on reduction of complex partial seizures (CPSs). Success is > or =50% fewer CPSs with a new AED or placebo; Overall Improvement is the success rate with drug minus the success rate with placebo. Adverse events were tabulated from product-labeling lists of COSTART items (incidence, > or =5%). The Summary Complaint score is the total number of reports of individual events for each AED. RESULTS: Efficacy data demonstrate differences in Overall Improvement rates among five new AEDs and placebos (p = 0.001). However, rates of response to placebo also differed significantly among trials (p = 0.01). Adverse events predominantly affect central nervous system, psychiatric, and general body systems. However, patients in the placebo control groups did not consistently report adverse effects. Summary Complaint scores differ among the five new AEDs, but variability in use of COSTART terms nullifies comparisons. CONCLUSIONS: Comparisons of data for five new AEDs provide information for selection among treatments when a second drug is needed to improve control of CPSs. However, significant differences among the control groups and other problems make comparisons between trials problematic. The final choice should be based on the need of the individual patient for superior seizure control versus minimal adverse effects. Publication Types: Review Review, tutorial PMID: 10386528, UI: 99313099

J Pharmacol Exp Ther 1999 Jul;290(1):214-9

Gabapentin attenuates nociceptive behaviors in an acute arthritis model in rats.

Lu Y, Westlund KN Department of Anatomy and Neuroscience and The Marine Biomedical Institute, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA.

In this study, we investigated the effectiveness of gabapentin (Neurontin), administered spinally with a microdialysis fiber, in reducing nociceptive behavioral responses induced by a knee joint inflammation model. This model is produced by injection of the knee joint with kaolin and carrageenan in rats. The resultant knee joint inflammation produces a secondary hyperalgesia to radiant heat applied to the hindpaw. Both pretreatment and post-treatment protocols were examined. Spinal administration of gabapentin (10 mg/ml) infused 1.5 h before induction of knee joint inflammation, although having no effect on the baseline, prevented the development of heat hyperalgesia. Gabapentin also prevented the development of other pain-related behaviors scored subjectively. Gabapentin had no effect, however, on the joint circumference increase typical in this model. In animals with fully developed knee joint inflammation, gabapentin produced a reversal of heat hyperalgesia. The paw withdrawal latency responses and subjective pain scores were no longer significantly different from baseline, but joint circumference increases remained. These data suggest that gabapentin is an effective antinociceptive agent when administered either before or after induction of knee joint inflammation acting through a central neurogenic mechanism. PMID: 10381778, UI: 99310843

Cell Mol Neurobiol 1999 Aug;19(4):511-32

Metabolism and excretion of mood stabilizers and new anticonvulsants.

Ketter TA, Frye MA, Cora-Locatelli G, Kimbrell TA, Post RM Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, California 94305-5723, USA.

1. The mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA), have differing pharmacokinetics, structures, mechanisms of action, efficacy spectra, and adverse effects. Lithium has a low therapeutic index and is renally excreted and hence has renally-mediated but not hepatically-mediated drug-drug interactions. 2. CBZ has multiple problematic drug-drug interactions due to its low therapeutic index, metabolism primarily by a single isoform (CYP3A3/4), active epoxide metabolite, susceptibility to CYP3A3/4 or epoxide hydrolase inhibitors, and ability to induce drug metabolism (via both cytochrome P450 oxidation and conjugation). In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, rendering it less susceptible to toxicity due to inhibition of its metabolism. However, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and increase free fractions of certain medications by displacing them from plasma proteins. 3. Older anticonvulsants such as phenobarbital and phenytoin induce hepatic metabolism, may produce toxicity due to inhibition of their metabolism, and have not gained general acceptance in the treatment of primary psychiatric disorders. 4. The newer anticonvulsants felbamate, lamotrigine, topiramate, and tiagabine have different hepatically-mediated drug-drug interactions, while the renally excreted gabapentin lacks hepatic drug-drug interactions but may have reduced bioavailability at higher doses. 5. Investigational anticonvulsants such as oxcarbazepine, vigabatrin, and zonisamide appear to have improved pharmacokinetic profiles compared to older agents. 6. Thus, several of the newer anticonvulsants lack the problematic drug-drug interactions seen with older agents, and some may even (based on their mechanisms of action and preliminary preclinical and clinical data) ultimately prove to have novel psychotropic effects. PMID: 10379423, UI: 99308231

Epilepsy Res 1999 Jun;35(2):109-21

Cognitive abilities and adjustment with gabapentin: results of a multisite study.

Dodrill CB, Arnett JL, Hayes AG, Garofalo EA, Greeley CA, Greiner MJ, Pierce MW Regional Epilepsy Center, Harborview Medical Center, Seattle, WA 98104-2499, USA. cdodrill@u.washington.edu

The cognitive and quality of life effects of gabapentin are not yet well explored. While preliminary work in the area has provided positive findings, a large double-blinded study has been needed to explore this area more thoroughly. From 24 sites in North America, 201 adults were studied who had uncontrolled complex partial seizures with or without secondary generalization. Attempts were made to convert each patient from one or two marketed antiepileptic drugs (AEDs) taken in baseline to gabapentin monotherapy (600, 1200, or 2400 mg/day). Tests of cognitive abilities and adjustment were administered at the end of the 8-week baseline period and at the end of the 26-week double-blind treatment period. Analyses of baseline to treatment period changes were conducted for each dose group in comparison with a reference group of placebo-treated patients from another study. In the area of cognitive functioning, no changes in any of the gabapentin groups were found in comparison with the reference group. In the area of adjustment and mood, however, improvement with gabapentin administration was noted on several variables pertaining to emotional and interpersonal adjustment. These results are consistent with findings from previous studies. PMID: 10372564, UI: 99299779

Pediatr Neurol 1999 May;20(5):381-2

Gabapentin for self-injurious behavior in Lesch-Nyhan syndrome.

McManaman J, Tam DA Department of Pediatrics and Clinical Investigations, Naval Medical Center San Diego, California 92134-1005, USA.

Self-injurious behavior is a common clinical problem in children with Lesch-Nyhan syndrome, an X-linked disorder of purine metabolism. This behavior is not observed in other conditions associated with increased serum concentrations of uric acid, hypoxanthine, and xanthine. Various neurotransmitters appear to play a pivotal role in self-injurious behavior. The authors present a patient with Lesch-Nyhan syndrome, whose self-injurious behavior was effectively treated with gabapentin, and discuss possible mechanisms of action. PMID: 10371385, UI: 99297795

Eur J Neurol 1999 Jul;6(4):505-507

A patient with multiple sclerosis and Down's syndrome with a rare paroxysmal symptom at onset.

Solaro C, Uccelli MM, Mancardi GL Department of Neurological Sciences and Rehabilitation, University of Genoa, Italy.

Down's syndrome (DS) is often associated with autoimmune diseases, although an association with multiple sclerosis (MS) has not been previously reported. A 49-year-old male with DS experienced progressively worsening gait and bladder dysfunction. Following Poser criteria, the patient was diagnosed with laboratory-supported definite MS. Ten days following diagnosis the patient experienced dysestetic paroxysmal pain at the pelvic level (an uncommon complaint in MS) which was initially addressed with carbamazepine, resulting in mild relief and adverse effects consisting of increased motor deficit and decreased daytime alertness. A titration combination of lamotrigine and gabapentin, two relatively new antiepileptic drugs which have been utilized individually for a number of neurological symptoms, resulted in significant reduction in pain frequency and intensity, with no adverse effects. This case study presents details of the first reported association of DS and MS, between which the pathogenetic relationship remains unclear. The presence of a rare symptom complaint in MS, as well as the effective combination of lamotrigine and gabapentin for treating this symptom, without adverse effects is an additional interesting aspect of this case. Copyright 1999 Lippincott Williams & Wilkins PMID: 10362908

Neuropharmacology 1999 May;38(5):611-23

Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn.

Boyce S, Wyatt A, Webb JK, O'Donnell R, Mason G, Rigby M, Sirinathsinghji D, Hill RG, Rupniak NM Merck Sharp Laboratory, Neuroscience Research Centre, Harlow, UK. susan_boyce@merck.com

The present study investigated the regional distribution of the N-methyl-D-aspartate (NMDA) receptor containing the NR2B subunit protein in rat lumbar spinal cord and examined whether selective NR2B antagonists would exhibit antinociception with reduced side-effect liability than subtype non-selective NMDA antagonists and anticonvulsants. Immunocytochemical studies showed the NR2B subunit had a restricted distribution, with moderate labelling of fibres in laminas I and II of the dorsal horn suggesting a presynaptic location on primary afferent fibers and possible involvement in pain transmission. In the in vivo studies, the NMDA/glycine antagonists (MK-801, 0.02-1 mg/kg i.p., L-687,414 10-300 mg/kg i.p., and L-701,324 1-10 mg/kg i.p.) and the anticonvulsant, gabapentin (10-500 mg/kg p.o.), induced rotarod deficits at antinociceptive doses. In contrast, the selective NR2B antagonists, (+/-)-CP-101,606 (1-100 mg/kg p.o.) and (+/-)-Ro 25-6981 (3-100 mg/kg i.p.) showed a significant dose window. (+/-)-CP-101,606 caused no motor impairment or stimulation in rats at doses up to 100 mg/kg p.o., which is far in excess of those inhibiting allodynia in neuropathic rats (ID50 4.1 mg/kg, p.o.). (+/-)-Ro 25-6981 also showed a significant separation (ID50 allodynia 3.8 mg/kg, i.p.), however, some disruption of rotarod performance was observed at 100 mg/kg. The anticonvulsant lamotrigine (3-500 mg/kg p.o.) also showed a good dose window. These findings demonstrate that NR2B antagonists may have clinical utility for the treatment of neuropathic and other pain conditions in man with a reduced side-effect profile than existing NMDA antagonists. PMID: 10340299, UI: 99271658

Pharmacotherapy 1999 May;19(5):565-72

Gabapentin: a review of published experience in the treatment of bipolar disorder and other psychiatric conditions.

Letterman L, Markowitz JS Department of Pharmacy Practice, Medical University of South Carolina, Charleston 29425, USA.

Successful therapy with valproate and carbamazepine in patients with psychiatric disorders led to investigation of other anticonvulsants for similar indications. Gabapentin is a relatively new anticonvulsant being investigated for potential use in the treatment of bipolar disorder (BD), anxiety disorders, behavioral dyscontrol, and substance use disorders. Its favorable side effect profile, absence of the need for therapeutic drug monitoring, and minimal drug interactions give gabapentin a potential role in these indications. Computer searches of the biomedical literature were undertaken to identify all pertinent case reports, case series, and studies of the drug as monotherapy or adjunctive therapy for BD; 10 reports were retrieved. In the treatment of various anxiety disorders, one study, one case report, and one case series were identified. At least one case series described gabapentin therapy for alcohol withdrawal and one case report of the drug for agitation associated with dementia. Published, well-designed studies evaluating the agent's effectiveness as monotherapy for BD are lacking. Its benefit as an adjunctive treatment with other mood stabilizers is also unestablished. Data regarding its efficacy in the treatment of anxiety disorders or manifestations of substance abuse are limited. These areas may deserve further investigation. Publication Types: Review Review, tutorial PMID: 10331819, UI: 99260662

Br J Pharmacol 1999 Apr;126(7):1634-8

Effects of anti-epileptic drugs on glutamine synthetase activity in mouse brain.

Fraser CM, Sills GJ, Forrest G, Thompson GG, Brodie MJ University Department of Medicine and Therapeutics, Western Infirmary, Glasgow.

1. Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate neurotransmission in the central nervous system. It is responsible for the conversion of glutamate to glutamine, and for the detoxification of ammonia. 2. We have investigated the effects of single and repeated intraperitoneal administration of a range of established and new anti-epileptic drugs on GS activity in mouse brain. 3. Four hours after the final dose, animals were sacrificed and the brains removed for analysis of GS activity. 4. Both single and repeated doses of phenytoin and carbamazepine were found to reduce enzyme activity (P<0.05). 5. Single doses of phenobarbitone, felbamate and topiramate were without effect, however repeated administration of these drugs dose-dependently reduced GS activity (P<0.05). 6. Single and repeated doses of sodium valproate, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam and desglycinyl-remacemide were found to have no effect on GS activity. 7. The reduction in enzyme activity demonstrated is unlikely to be related to the anti-epileptic actions of these drugs, but may contribute to their toxicity. PMID: 10323596, UI: 99255196

Epilepsy Res 1999 May;35(1):13-20

Gabapentin modifies extracellular opioid peptide content in amygdala: a microdialysis study.

Rocha L, Ondarza-Rovira R, Maidment NT Instituto Mexicano de Psiquiatria, Division de Neurociencias, Mexico, D.F. rocha@cenids.ssa.gob.mx

Opioid peptide release was monitored in the amygdala and hippocampus of freely moving rats following a single oral administration of gabapentin using microdialysis. Extracellular opioid peptide levels were elevated above basal levels in the amygdala within the first 60 (54%) and 90 min (68%) after gabapentin administration. Levels returned to basal conditions 120 min following the treatment. No significant changes were detected in the hippocampus. The majority of immunoreactive material recovered from the amygdala following gabapentin administration was identified as Leu-enkephalin and Met-enkephalin by high performance liquid chromatography (HPLC) analysis. It is proposed that the enhanced opioid peptide release in the amygdala induced by gabapentin might be involved with the antiepileptic effects as well as with some adverse events produced by this drug. PMID: 10232790, UI: 99247775

Pharm Res 1999 Apr;16(4):519-26

Transport of pregabalin in rat intestine and Caco-2 monolayers.

Jezyk N, Li C, Stewart BH, Wu X, Bockbrader HN, Fleisher D College of Pharmacy, The University of Michigan, Ann Arbor 48109-1065, USA.

PURPOSE: The purpose of this study was to determine if the intestinal transport of pregabalin (isobutyl gamma-aminobutyric acid, isobutyl GABA), a new anticonvulsant drug, was mediated by amino acid carriers with affinity for large neutral amino acids (LNAA). METHODS: Pregabalin transport was studied in rat intestine and Caco-2 monolayers. An in vitro Ussing/diffusion chamber model and an in situ single-pass perfusion model were used to study rat intestinal transport. An in vitro diffusion chamber model was used to evaluate Caco-2 transport. RESULTS: In rat ileum, pregabalin transport was saturable and inhibited by substrates of intestinal LNAA carriers including neurontin (gabapentin), phenylalanine, and proline. Weak substrates of intestinal LNAA carriers (beta-alanine, gamma-aminobutyric acid, and methyl aminoisobutyric acid) did not significantly change pregabalin transport. In Caco-2 monolayers that showed a high capacity for phenylalanine transport, pregabalin transport was concentration- and direction-independent and equivalent in magnitude to the paracellular marker, mannitol. The in vitro and in situ rat ileal permeabilities of the LNAA carrier-mediated compounds neurontin, pregabalin, and phenylalanine correlated well with the corresponding in vivo human oral absorption. CONCLUSIONS: The transport of pregabalin was mediated by LNAA carriers in rat ileum but not in Caco-2 monolayers. Caco-2 was not an appropriate model for evaluating the in vivo human oral absorption of pregabalin and neurontin. PMID: 10227706, UI: 99242265

Eur J Pharmacol 1999 Mar 26;369(3):335-8

Gabapentin decreases the severity of dystonia at low doses in a genetic animal model of paroxysmal dystonic choreoathetosis.

Richter A, Loscher W Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany. arichter@pharma.tiho-hannover.de

The effects of the gamma-aminobutyric acid (GABA)-potentiating drug gabapentin (1-(aminomethyl) cyclohexaneacetic acid) on severity of dystonia were examined in a hamster model of idiopathic paroxysmal dystonic choreoathetosis. In the genetically dystonic hamster (dt(sz)) recent pharmacological and neurochemical studies suggested that disturbed GABAergic inhibition is involved in the pathogenesis. In line with a case report of beneficial effects in human paroxysmal dystonic choreoathetosis, gabapentin reduced the severity of dystonia in mutant hamsters at doses of 5 and 10 mg kg(-1) i.p. At higher doses (20 and 100 mg kg(-1)), gabapentin, however, failed to exert antidystonic effects. The GABApotentiating activity of gabapentin could explain the antidystonic effects of low doses, while the loss of efficacy at higher doses may be due to other mechanisms of gabapentin. PMID: 10225372, UI: 99239878

J Clin Psychiatry 1999 Apr;60(4):245-8

Clinical experience with gabapentin in patients with bipolar or schizoaffective disorder: results of an open-label study.

Cabras PL, Hardoy MJ, Hardoy MC, Carta MG Department of Neurological and Psychiatric Sciences, University of Florence, Italy.

BACKGROUND: This study was carried out to evaluate the efficacy, tolerability, and safety of gabapentin as an adjunctive treatment in patients with bipolar or schizoaffective disorder with manic or hypomanic symptoms. METHOD: Twenty-five patients fulfilling DSM-IV diagnostic criteria for bipolar I disorder or schizoaffective disorder underwent a 16-week, open-trial treatment with gabapentin. Symptom severity was measured using the Clinical Global Impressions scale (CGI) and the Brief Psychiatric Rating Scale (BPRS). Baseline scores and final scores were compared by using the Student t test and the Friedman range variance analysis. RESULTS: Twenty-two patients (88%) completed the 16 weeks of treatment with gabapentin; 19 (76%) had a positive response as measured by changes in CGI and BPRS scores. The mean dose was 1440 mg/day. The only side effect observed was oversedation, which decreased with continuing treatment. CONCLUSION: Gabapentin was effective in the treatment of mania and hypomania in patients with bipolar and schizoaffective disorders. If confirmed in controlled studies, these findings suggest that gabapentin represents a well-tolerated, rapidly acting antimanic agent. Publication Types: Clinical trial PMID: 10221286, UI: 99236475

Pediatr Neurol 1999 Mar;20(3):195-7

Development of two stable oral suspensions for gabapentin.

Nahata MC College of Pharmacy, Ohio State University, Columbus 43210, USA.

Gabapentin is not available in a liquid dosage form for clinical use. This study was designed to develop two oral gabapentin suspensions and determine their stability under refrigeration or at room temperature. Commercially available gabapentin capsules were used to prepare two suspensions: one in extemporaneously prepared 1% methylcellulose in syrup (1:1) and another in equal volumes of commercially available suspending agents/syrup (Ora Plus/Ora Sweet). Each suspension containing gabapentin (100 mg/mL) was stored in 10 plastic prescription bottles; five were stored at 4 degrees C and five at 25 degrees C. Three 500-microL samples were collected immediately after preparation (day 0) and on days 7, 14, 28, 42, 56, 70, and 91. Gabapentin was measured by accurate, reproducible, specific, and stability-indicating high-performance liquid chromatography (n = 15). The observed mean concentrations exceeded 90% of the initial concentrations in both suspensions for 91 days at 4 degrees C and 56 days at 25 degrees C. No change in pH, odor, or physical appearance was observed. On the basis of these results, stable oral suspensions of gabapentin can be prepared and stored in plastic prescription bottles for 91 days at 4 degrees C or 56 days at 25 degrees C. PMID: 10207927, UI: 99224334

Arch Neurol 1999 Apr;56(4):475-80

A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor.

Gironell A, Kulisevsky J, Barbanoj M, Lopez-Villegas D, Hernandez G, Pascual-Sedano B Department of Neurology, Sant Pau Hospital, Autonomous University of Barcelona, Spain.

BACKGROUND: New medication is needed to treat essential tremor. Preliminary evidence suggests that gabapentin may be effective in the treatment of this disorder. OBJECTIVE: To study the effects of gabapentin in a comparative, double-blind, crossover, placebo-controlled trial of patients who have essential tremor. PATIENTS AND METHODS: 16 patients with essential tremor (6 with a new onset and 10 with a 2-week washout period of previous treatment with propranolol hydrochloride) received gabapentin (Neurontin), 400 mg 3 times daily; propranolol hydrochloride, 40 mg 3 times daily; and placebo for 15 days with a 1-week washout period between treatments. MAJOR OUTCOME MEASURES: Major outcome evaluations consisted of a Tremor Clinical Rating Scale, accelerometric recordings, and a self-reported disability scale obtained before drug intake on study days 1 and 15 of each treatment period. In addition, the initial (day 1) and superimposed (day 15) drug effects were studied before and 2, 4, 6, and 8 hours after drug intake. RESULTS: At day 15, both gabapentin and propranolol demonstrated significant and comparable efficacy in reducing tremor from baseline in all tremor measures. The initial drug effects evaluated through accelerometry revealed no significant changes with the use of a placebo, but gabapentin and propranolol use significantly reduced tremor power. CONCLUSION: Gabapentin may be useful for the treatment of essential tremor. Publication Types: Clinical trial Randomized controlled trial PMID: 10199338, UI: 99213430

Med Res Rev 1999 Mar;19(2):149-77

3-substituted GABA analogs with central nervous system activity: a review.

Bryans JS, Wustrow DJ Parke-Davis Neuroscience Research Center, Forvie Site, Cambridge, UK.

Gabapentin and Pregabalin are both 3-alkylated gamma-amino butyric acid (GABA) analogs. Gabapentin was designed as a lipophilic GABA analog and was first synthesized as a potential anticonvulsant and was launched in 1994 as add-on therapy for the treatment of epilepsy. In this review the discovery and development of gabapentin as an anticonvulsant are discussed. During human trials and while in clinical use, it became apparent that gabapentin induced some other potentially useful therapeutic effects in chronic pain states and behavioral disorders. A review of animal and clinical data relating to these other potential therapeutic utilities is presented. Pregabalin was identified after an investigation into other 3-substituted GABA analogs. It has since been shown to have a similar pharmacological profile to gabapentin with greater potency in preclinical models of pain and epilepsy. Studies of the mechanism(s) of action of these compounds are discussed. Work towards identifying new analogs of both gabapentin and pregabalin is also reviewed. Publication Types: Review Review, tutorial PMID: 10189176, UI: 99203059

Curr Opin Neurol 1999 Feb;12(1):21-7

Neuropharmacologic aspects of the ocular motor system and the treatment of abnormal eye movements.

Leigh RJ, Ramat S Department of Neurology, Veterans Affairs Medical Center, Cleveland, Ohio, USA. rjl4@po.cwru.edu

Neuropharmacology is aiding our understanding of the control of eye movements in at least three ways. First, neurotransmitters have been identified in the pathways that coordinate gaze. Second, the technique of pharmacologic inactivation has provided a powerful method to determine the contributions of populations of neurons to specific behaviors, such as steady gaze holding. Finally, the results of basic neuropharmacologic studies have been used to identify candidate drugs for therapeutic trials of abnormal eye movements. Publication Types: Review Review, tutorial PMID: 10097880, UI: 99197953

Epilepsia 1999 Apr;40(4):474-9

Effects of age and gender on single-dose pharmacokinetics of gabapentin.

Boyd RA, Turck D, Abel RB, Sedman AJ, Bockbrader HN Department of Pharmacokinetics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan, USA.

PURPOSE: This study was conducted to evaluate the effect of age, age-related changes in renal function, and gender on the single-dose pharmacokinetics of orally administered gabapentin (GBP). METHODS: The pharmacokinetics of a single 400-mg oral dose of GBP were studied in 36 healthy subjects (18 men and 18 women) aged 20-78 years. Serial blood samples and total urine output were collected for 48 h after the dose. GBP concentrations in plasma and urine were measured by high-performance liquid chromatography, and pharmacokinetic parameters were calculated by noncompartmental methods. RESULTS: All subjects tolerated the drug well, with only mild symptoms reported. No change in maximal GBP plasma concentration (Cmax), time at which Cmax occurred (tmax), or apparent volume of distribution (V/F) with age was noted. A significant linear decline in apparent oral clearance (CL/F), elimination-rate constant (lambda z), and renal clearance (CLR) with increasing age was observed (p < 0.005). Because total urinary recovery of unchanged drug (an estimate of F for GBP) did not change with age, the decline in CL/F and lambda z can be explained by the decline in CLR. The only pharmacokinetic parameter that was significantly different between genders was Cmax, which was approximately 25% higher for women than for men (p = 0.016), consistent with gender differences in body size. CONCLUSIONS: The results of this study suggest that changes in renal function are responsible for age-related changes in GBP pharmacokinetics. Reduction of GBP dosage may be required in elderly patients with reduced renal function. The pharmacokinetics of GBP are similar in men and women. PMID: 10219274, UI: 99236014

Acta Otorrinolaringol Esp 1999 Mar 1;50(2):175-177

[Use of gabapentin in glossopharyngeal neuralgia].

Garcia Callejo FJ, Marco Algarra J, Talamantes Escriba F, Martinez Beneyto MP, Esparcia Navarro M, Morant Ventura A Servicio de ORL,Hospital Clinico Universitario,Valencia,Valencia,Espana.

Anticonvulsant drugs, especially carbamazepine, are the treatment of choice for glossopharyngeal neuralgia. If no clinical response is obtained, surgical treatment, including nerve section or decompression, may be required. We report the results obtained with a new anticonvulsant, gabapentin, as an alternative for cases of carbamazepine failure. In 7 patients with bouts of glosso- pharyngeal neuralgia refractory to the usual medical treatment, gabapentin produced improvement in 5 patients. Response was poor in patients who had undergone surgical nerve decompression. Gabapentin was concluded to be an effective therapeutic option for neuralgia of the IXth cranial nerve before surgery. PMID: 10217696

Eur Neuropsychopharmacol 1999 Mar;9(3):257-8

Gabapentin as monotherapy in the treatment of acute mania.

Hatzimanolis J, Lykouras L, Oulis P, Christodoulou GN Department of Psychiatry, University of Athens, Eginition Hospital, Greece.

Two cases of mania treated with gabapentin, a new anticonvulsant, are presented. After 2 weeks of treatment a moderate improvement of both patients was observed. The antimanic effect of gabapentin awaits confirmation by systematic, well designed studies. PMID: 10208297, UI: 99222978

Reg Anesth Pain Med 1999 Mar-Apr;24(2):170-4

Acute herpetic neuralgia and postherpetic neuralgia in the head and neck: response to gabapentin in five cases.

Filadora VA 2nd, Sist TC, Lema MJ Department of Anesthesiology and Pain Medicine, Roswell Cancer Institute, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 14263, USA.

BACKGROUND AND OBJECTIVES: The clinical presentations and pharmacologic management of three patients with acute herpetic neuralgia (AHN) and two patients with postherpetic neuralgia (PHN), confined to the head and neck region, are described. METHODS: Two patients had pain in the ophthalmic division of the trigeminal nerve, two had pain confined to the C2-C4 dermatomes, and one patient had C2 pain with radiating and referred pain to the second and third divisions of the trigeminal nerve. RESULTS: Gabapentin, an anticonvulsant drug, was effective in treating these patients, including the two cases of AHN. All patients reported complete pain relief after titration with gabapentin up to 1,800 mg/d. The patients noted a dose-dependent decrease in pain almost immediately after starting gabapentin. Specifically, reduction in the frequency and intensity of allodynia, burning pain, shooting pain, and throbbing pain were noted. None of the patients experienced side effects from the drug. CONCLUSIONS: In view of the results in these patients, blinded, controlled studies are needed to determine the efficacy of gabapentin for treating AHN and PHN. PMID: 10204905, UI: 99219599

Pain 1999 Mar;80(1-2):391-8

Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat.

Field MJ, McCleary S, Hughes J, Singh L Department of Biology, Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, UK.

A single injection of streptozocin (50 mg/kg, i.p.) led to the development of static and dynamic allodynia in the rat. The two responses were detected, respectively, by application of pressure using von Frey hairs or lightly stroking the hind paw with a cotton bud. Static allodynia was present in the majority of the animals within 10 days following streptozocin. In contrast, dynamic allodynia took almost twice as long to develop and was only present in approximately 60% of rats. Morphine (1-3 mg/kg, s.c.) and amitriptyline (0.25-2.0 mg/kg, p.o.) dose-dependently blocked static allodynia. However, neither of the compounds was effective against dynamic allodynia. In contrast, gabapentin (10-100 mg/kg, p.o.) and the related compound pregabalin (3-30 mg/kg, p.o.) dose-dependently blocked both types of allodynia. However, the corresponding R-enantiomer (10-100 mg/kg, p.o.) of pregabalin, was found to be inactive. The intrathecal administration of gabapentin dose-dependently (1-100 microg/animal) blocked both static and dynamic allodynia. In contrast, administration of similar doses of gabapentin into the hind paw failed to block these responses. It is suggested that in this model of neuropathic pain dynamic allodynia is mediated by A beta-fibres and the static type involves small diameter nociceptive fibres. These data suggest that gabapentin and pregabalin possess a superior antiallodynic profile than morphine and amitriptyline, and may represent a novel class of therapeutic agents for the treatment of neuropathic pain. PMID: 10204753, UI: 99219447

Neurosci Lett 1999 Mar 5;262(2):101-4

Gabapentin prevents hyperalgesia during the formalin test in diabetic rats.

Cesena RM, Calcutt NA Department of Pathology, University of California San Diego, La Jolla 92024-0612, USA.

The anticonvulsant agent gabapentin exhibits antihyperalgesic properties in animal models of neuropathic pain. Diabetic rats display increased nocifensive behavior during the formalin test of persistent chemical irritation to the paw, suggesting the presence of abnormal pain processing mechanisms. We therefore, investigated the efficacy of gabapentin on formalin-evoked behavior in diabetic rats. Diabetic rats showed increased (P < 0.05) flinching during the normally quiescent phase of the 5.0% formalin test. Gabapentin (50 mg/kg i.p. 30 min pre-test) suppressed flinching during phases 1 and 2 of the formalin test in both control and diabetic rats but not the increased flinching of diabetic rats during the quiescent phase. When 0.5% formalin was used, diabetic rats exhibited increased flinching during both the quiescent phase and phase 2. Gabapentin was without effect in controls but suppressed (P < 0.01) the increased flinching in diabetic rats. Gabapentin displays efficacy against abnormal sensory processing in diabetic rats and may be of benefit for treating painful diabetic neuropathy. PMID: 10203241, UI: 99217904

Arch Neurol 1999 Apr;56(4):475-80

A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor.

Gironell A, Kulisevsky J, Barbanoj M, Lopez-Villegas D, Hernandez G, Pascual-Sedano B Department of Neurology, Sant Pau Hospital, Autonomous University of Barcelona, Spain.

BACKGROUND: New medication is needed to treat essential tremor. Preliminary evidence suggests that gabapentin may be effective in the treatment of this disorder. OBJECTIVE: To study the effects of gabapentin in a comparative, double-blind, crossover, placebo-controlled trial of patients who have essential tremor. PATIENTS AND METHODS: 16 patients with essential tremor (6 with a new onset and 10 with a 2-week washout period of previous treatment with propranolol hydrochloride) received gabapentin (Neurontin), 400 mg 3 times daily; propranolol hydrochloride, 40 mg 3 times daily; and placebo for 15 days with a 1-week washout period between treatments. MAJOR OUTCOME MEASURES: Major outcome evaluations consisted of a Tremor Clinical Rating Scale, accelerometric recordings, and a self-reported disability scale obtained before drug intake on study days 1 and 15 of each treatment period. In addition, the initial (day 1) and superimposed (day 15) drug effects were studied before and 2, 4, 6, and 8 hours after drug intake. RESULTS: At day 15, both gabapentin and propranolol demonstrated significant and comparable efficacy in reducing tremor from baseline in all tremor measures. The initial drug effects evaluated through accelerometry revealed no significant changes with the use of a placebo, but gabapentin and propranolol use significantly reduced tremor power. CONCLUSION: Gabapentin may be useful for the treatment of essential tremor. Publication Types: Clinical trial Randomized controlled trial PMID: 10199338, UI: 99213430

Cleve Clin J Med 1999 Apr;66(4):239-45

Hypersensitivity syndrome to antiepileptic drugs: a review including new anticonvulsants.

Hamer HM, Morris HH Department of Neurology, University of Marburg, Germany.

Anticonvulsant hypersensitivity syndrome, a potentially fatal but rare reaction, manifests as rash, fever, tender lymphadenopathy, hepatitis, and eosinophilia. To manage hypersensitivity syndrome successfully, one must recognize the symptoms early, stop the offending drug immediately, and substitute a safe, alternative anticonvulsant medication. Hypersensitivity syndrome has not been described in patients taking benzodiazepines or the newer anticonvulsants gabapentin or topiramate, and these appear to be safe substitutes for drugs that cause the reaction. Publication Types: Review Review, tutorial PMID: 10199060, UI: 99215273

Med Res Rev 1999 Mar;19(2):149-77

3-substituted GABA analogs with central nervous system activity: a review.

Bryans JS, Wustrow DJ Parke-Davis Neuroscience Research Center, Forvie Site, Cambridge, UK.

Gabapentin and Pregabalin are both 3-alkylated gamma-amino butyric acid (GABA) analogs. Gabapentin was designed as a lipophilic GABA analog and was first synthesized as a potential anticonvulsant and was launched in 1994 as add-on therapy for the treatment of epilepsy. In this review the discovery and development of gabapentin as an anticonvulsant are discussed. During human trials and while in clinical use, it became apparent that gabapentin induced some other potentially useful therapeutic effects in chronic pain states and behavioral disorders. A review of animal and clinical data relating to these other potential therapeutic utilities is presented. Pregabalin was identified after an investigation into other 3-substituted GABA analogs. It has since been shown to have a similar pharmacological profile to gabapentin with greater potency in preclinical models of pain and epilepsy. Studies of the mechanism(s) of action of these compounds are discussed. Work towards identifying new analogs of both gabapentin and pregabalin is also reviewed. PMID: 10189176, UI: 99203059

Br J Pharmacol 1999 Feb;126(3):689-96

An in vitro electrophysiological study on the effects of phenytoin, lamotrigine and gabapentin on striatal neurons.

Calabresi P, Centonze D, Marfia GA, Pisani A, Bernardi G Dip. Sanita, Universita di Roma Tor Vergata, Rome, Italy. calabre@uniroma2.it

We performed intracellular recordings from a rat corticostriatal slice preparation in order to compare the electrophysiological effects of the classical antiepileptic drug (AED) phenytoin (PHT) and the new AEDs lamotrigine (LTG) and gabapentin (GBP) on striatal neurons. PHT, LTG and GBP affected neither the resting membrane potential nor the input resistance/membrane conductance of the recorded cells. In contrast, these agents depressed in a dose-dependent and reversible manner the current-evoked repetitive firing discharge. These AEDs also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) evoked by cortical stimulation. However, substantial pharmacological differences between these drugs were found. PHT was the most effective and potent agent in reducing sustained repetitive firing of action potentials, whereas LTG and GBP preferentially inhibited corticostriatal excitatory transmission. Concentrations of LTG and GBP effective in reducing EPSPs, in fact, produced only a slight inhibition of the firing activity of these cells. LTG, but not PHT and GBP, depressed cortically-evoked EPSPs increasing paired-pulse facilitation (PPF) of synaptic transmission, suggesting that a presynaptic site of action was implicated in the effect of this drug. Accordingly, PHT and GBP, but not LTG reduced the membrane depolarizations induced by exogenously-applied glutamate, suggesting that these drugs preferentially reduce postsynaptic sensitivity to glutamate released from corticostriatal terminals. These data indicate that in the striatum PHT, LTG and GBP decrease neuronal excitability by modulating multiple sites of action. The preferential modulation of excitatory synaptic transmission may represent the cellular substrate for the therapeutic effects of new AEDs whose use may be potentially extended to the therapy of neurodegenerative diseases involving the basal ganglia. PMID: 10188980, UI: 99202863

Epilepsy Res 1999 Feb;33(2-3):169-76

The reduction in paired-pulse inhibition in the rat hippocampus by gabapentin is independent of GABA(B) receptor receptor activation.

Stringer JL, Lorenzo N Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA. janets@bcm.tmc.edu

Previously we have shown that gabapentin causes a reduction of paired-pulse inhibition in the dentate gyrus of the urethane-anesthetized rat, which looks very much like the effect of baclofen on paired-pulse inhibition. In addition, it has been proposed that gabapentin increases release of GABA from non-vesicular stores and may, therefore, interact with GABA(B) mechanisms. Here we tested the ability of a GABA(B) agonist, baclofen, and a GABA(B) antagonist, CGP35348, to block the effect of gabapentin on paired-pulse inhibition in the dentate gyrus in urethane-anesthetized adult Sprague-Dawley rats. Both baclofen (6 mg/kg) and gabapentin (100 mg/kg) caused a long-lasting reduction of paired-pulse inhibition in the dentate gyrus when given alone or in combination. CGP35348 (45 mg/kg) blocked the effect of baclofen on paired-pulse inhibition, but did not alter the effect of gabapentin. Gabapentin also caused a reduction of inhibition in the CA1 region, indicating that its effect is not specific for the dentate gyrus. These results suggest that gabapentin produces its effect on paired-pulse inhibition independent from the effect of baclofen and not through non-vesicular release of GABA interacting with the GABA(B) receptor system. PMID: 10094428, UI: 99192251

Fortschr Neurol Psychiatr 1999 Feb;67(2):75-80

[Predictors of response to phase prophylactics (mood stabilizers) in bipolar affective disorders].

Walden J, Normann C, Langosch J, Grunze H Universitatsklinik fur Psychiatrie und Psychosomatik, Abt. fur Psychiatrie und Psychotherapie der Universitat Freiburg.

Since the introduction of lithium ions in the acute treatment and in the prophylaxis of bipolar disorders the antiepileptic drugs valproate and carbamazepine have been in use for several years as mood stabilizers. In a number of open and controlled clinical studies predictors of response for the single drugs were investigated. These studies indicated that valproate was a predictor of good response in mixed (dysphoric) mania and bipolar rapid cycling. Moreover, valproate has a better response than lithium in secondary mania (organic origin) and atypical mania (episode sequence: depression-mania-euthymia rather than mania-depression-euthymia). The preferential efficacy in the spectrum of bipolar disorders of the new antiepileptic drugs lamotrigine and gabapentin must be analysed in more detail in future studies. Publication Types: Review Review, tutorial PMID: 10093780, UI: 99193740

Postgrad Med 1999 Mar;105(3):59-61, 65-6, 73-4

How to help patients with restless legs syndrome. Discerning the indescribable and relaxing the restless.

Evidente VG, Adler CH Parkinson's Disease and Movement Disorders Center, Mayo Clinic Scottsdale, AZ 85259, USA.

Restless legs syndrome is a common, potentially disabling condition that affects about 10% to 15% of the general population and yet is often unrecognized and misdiagnosed. It is mainly diagnosed clinically and only rarely requires polysomnography. The condition is usually primary and treatable. First, however, secondary causes should be sought, especially iron deficiency and peripheral neuropathy, because when the source is an accompanying factor or condition, the syndrome may be curable. The most effective drugs are dopaminergic agents, clonazepam, opioids, gabapentin, and clonidine. Additional agents are available that may be beneficial as add-on or alternative therapy. Publication Types: Review Review literature PMID: 10086034, UI: 99185953

J Am Pharm Assoc (Wash) 1999 Mar-Apr;39(2):217-21

Treatment of postherpetic neuralgia.

Menke JJ, Heins JR South Dakota State University, Brookings 57007-0099, USA. menke.jennifer_@sioux-falls.va.gov

OBJECTIVE: To review treatment options for postherpetic neuralgia (PHN). DATA SOURCES: Clinical literature selected by the authors accessed via MEDLINE. Search terms included postherpetic neuralgia, capsaicin, antidepressants, anticonvulsants, and lidocaine. STUDY SELECTION: Controlled trials relevant to PHN. DATA SYNTHESIS: Traditional analgesics offer little benefit for the treatment of PHN. The best results for pain relief have come from capsaicin and tricyclic antidepressants. Anticonvulsants have also been used, although the number of studies evaluating this is limited. More invasive therapies, such as transcutaneous electrical nerve stimulation and nerve blocks, can be considered if other therapies fail. CONCLUSION: Early diagnosis and treatment of herpes zoster may offer patients the best chance of preventing the development of PHN. However, if PHN does develop, the patient should seek treatment early for the best chance of pain relief. Publication Types: Review Review, tutorial PMID: 10079653, UI: 99179370

Ther Drug Monit 1999 Feb;21(1):137-8

Skin eruption with gabapentin in a patient with repeated AED-induced Stevens-Johnson's syndrome.

DeToledo JC, Minagar A, Lowe MR, Ramsay RE Department of Neurology, University of Miami, Florida 33136, USA.

Skin eruptions have been reported with the use of all antiepileptic drugs and there is a significant risk of cross-reactivity between these agents in causing serious eruptions such as Stevens-Johnson's syndrome. Gabepentin is usually considered a safe agent for patients with a previous history of drug allergies and there have been no cases of skin eruption reported to the gabapentin post marketing surveillance. We report a patient who had severe Stevens-Johnson's syndrome induced by phenytoin and later by carbamazepine. Subsequent use of gabapentin also resulted in a skin eruption which was limited to the lower extremities but without systemic or mucosal involvement. This case suggests that patients with a strong history of drug-induced idiosyncratic reactions may experience such reactions to gabapentin as well. PMID: 10051068, UI: 99158355

Pharmacotherapy 1999 Feb;19(2):223-7

Increased risk of erythema multiforme major with combination anticonvulsant and radiation therapies.

Micali G, Linthicum K, Han N, West DP Department of Dermatology, University of Catania, Italy.

Erythema multiforme major (EMM; Stevens-Johnson syndrome) is a cutaneous disorder associated with a wide variety of factors including ingestion of drugs such as phenytoin and exposure to intracranial radiation therapy. Based on observations of a 47-year-old black man with brain metastases who developed EMM after combined phenytoin and radiation therapy, we conducted a MEDLINE literature search for articles on similar cases from 1966 to the present. Twenty cases were identified that support the hypothesis that EMM is associated with combined phenytoin and radiation therapy. The reaction, or its severity, has no relationship to the phenytoin or radiation therapy dosage, or to the histologic type of brain tumor. Also, EMM has no apparent age or gender predisposition in association with phenytoin-radiation therapy. Thus this is a clinical phenomenon that occurs with unusual frequency in patients with brain tumor who undergo radiation therapy while taking phenytoin. Phenytoin and other anticonvulsants such as phenobarbital and carbamazepine induce cytochrome P450 3A and produce oxidative reactive intermediates that may be implicated in hypersensitivity reactions such as EMM. Both carbamazepine and barbiturates have shown cross-sensitivity with phenytoin; furthermore, a case of EMM in a patient receiving carbamazepine and whole brain radiation therapy has been reported. As carbamazepine, valproate, and barbiturates have been associated with EMM, gabapentin may be considered as alternative anticonvulsant therapy when appropriate. Publication Types: Review Review of reported cases PMID: 10030773, UI: 99153844

J Pharmacol Exp Ther 1999 Mar;288(3):1026-30

Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats.

Pan HL, Eisenach JC, Chen SR Department of Anesthesiology, Physiology, and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1009, USA. hpan@wfubmc.edu

Repetitive ectopic discharges from injured afferent nerves play an important role in initiation and maintenance of neuropathic pain. Gabapentin is effective for treatment of neuropathic pain but the sites and mechanisms of its antinociceptive actions remain uncertain. In the present study, we tested a hypothesis that therapeutic doses of gabapentin suppress ectopic afferent discharge activity generated from injured peripheral nerves. Mechanical allodynia, induced by partial ligation of the sciatic nerve in rats, was determined by application of von Frey filaments to the hindpaw. Single-unit afferent nerve activity was recorded proximal to the ligated sciatic nerve site. Intravenous gabapentin, in a range of 30 to 90 mg/kg, significantly attenuated allodynia in nerve-injured rats. Furthermore, gabapentin, in the same therapeutic dose range, dose-dependently inhibited the ectopic discharge activity of 15 injured sciatic afferent nerve fibers through an action on impulse generation. However, the conduction velocity and responses of 12 normal afferent fibers to mechanical stimulation were not affected by gabapentin. Therefore, this study provides electrophysiological evidence that gabapentin is capable of suppressing the ectopic discharge activity from injured peripheral nerves. This action may contribute, at least in part, to the antiallodynic effect of gabapentin on neuropathic pain. PMID: 10027839, UI: 99152160

Clin Podiatr Med Surg 1999 Jan;16(1):67-79

Diagnostic algorithms for neuromuscular diseases.

Manon-Espaillat R, Mandel S Department of Neurology, Jefferson Medical College, Philadelphia, Pennsylvania, USA.

Neuromuscular disorders can impose significant disability in patients by virtue of weakness, pain, and sensory and autonomic symptoms and deficits. For all of these disorders, supportive measures, appropriate physical therapy, and respiratory support are beneficial. Pain management can be accomplished by the use of antiepileptic medications, such as carbamazepine, phenytoin, valproic, and gabapentin. Tricyclic antidepressants can also be helpful for pain management and depression. Benzodiazepines and baclofen are helpful for management of spasticity. No specific treatment exists yet for the motor neuron disorders. In peripheral neuropathies, identifying and treating the cause is most important. In other neuropathies, such as in acute or chronic inflammatory demyelinating neuropathies, immunosuppression is indicated. Myasthenia gravis can be treated with cholinesterase inhibitors and immunosuppression. A specific treatment does not exist yet for muscular dystrophies. Immunosuppression is helpful in patients with inflammatory myopathies. Toxic myopathies can be treated by removing the causative agent and by supportive measures. Endocrine myopathies will respond to treatment of the primary endocrinopathy. Publication Types: Review Review, tutorial PMID: 9929772, UI: 99128633

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