Gabapentin: Neuropathic Pain and Body Weight Gain

Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway New Jersey, 08854

p>Gabapentin (Neurontin) is commonly used by many people for chronic neuropathic pain. Recent posts on the CareCure web site suggested that gabapentin may cause body weight gain. While this effect of gabapentin is seldom mentioned as a gabapentin side-effect (i.e. http://www.canadiandrugs.ca/gabapentin.htm) and is briefly mentioned in some lists (i.e. http://bipolar.about.com/cs/sfx/a/sfx_neurontin.htm), body weight gain is a well-documented complication of long-term gabapentin use. This is a review of the literature on this subject.

Gabapentin was first developed to treat epilepsy and recently discovered to have some beneficial effects for neuropathic pain. The drug is remarkably non-toxic. Studies of developmental toxicity in pregnant animals at doses of 500-3000 mg/kg (mice) and 60-1500 mg/kg (rats and rabbits) revealed no adverse maternal or fetal effects in mice or rats but at 1500 mg/kg, one rabbit died, four aborted, and the rest had reduced food consumption and body weight gain, while the rabbit fetuses showed no significant effect of the drug (Petrere and Anderson, 1994).

Early clinical studies suggested that gabapentin can cause weight gain in a small percentage of patients. In 1995, Morris (Morris, 1995) studied 100 patients (47 men and 53 women) who took a variety of anticonvulsant drugs, including gabapentin. Gabapentin reduced seizures by more than 50% in 72 patients and 23 patients had 75% reduction of seizures; 57% continued gabapentin treatment and 5 remained seizure-free on gabapentin monotherapy without complication. The mean daily dose was 2107 mg. Transient fatigue was the most common side-effect, affecting 20 patients. Seven patients had ataxia but 6 of these were taking another anti-seizure drug (carbamazepine). Two of the patients experienced wight gain.

Subsequent studies showed that high-dose long-term treatment of gabapentin causes weight gain in a small percentage of epileptic patients. In 1997, DeToledo, et al. (DeToledo, et al., 1997) reported that epileptic patients who received gabapentin doses greater than 3000 mg/day for 12 months or longer had weight gain. In 44 patients, 10 (23%) had greater than 10% body weight gain, 15 (34%) had 5-10% body weight gain, 16 (36%) had no change, and 3 (7%) lost 5-10% body weight. Body weight gain occurred in patients taking gabapentin with other drugs but also in those taking gabapentin alone. In 1998, Baulac, et al. (Baulac, et al., 1998) studied 610 patients receiving 900-2400 mg/day of gabapentin for 6 months and only 8.8% of the patients showed weight gain. Postmarketing surveillance of 3100 patients in England suggest similar results (Wilton and Shakir, 2002).

Animal studies had not shown weight gain as a consistent effect of gabapentin. Long-term exposure to high-dose gabapentin in fact appears to suppress weight gain in rats. In 1995, Sigler, et al. (Sigler, et al., 1995) did a 2-year tumor bioassay in male Wistar rats, fed 250, 1000, and 2000 mg/kg doses for 104 weeks. While treatment resulted in 8-16% incidence of pancreatic acinar neoplasia, there were no increase in other tumor types and there was no tumor increase in female rats. The tumors were not invasive, did not metastasize, and did not increase mortality. Rats receiving 1000 and 2000 mg/kg showed body weight suppression.

The weight gain produced by gabapentin is similar to that produced by other drugs such as propranolol, atenelol, verapamil, and valproate, affecting only a modest number of patients (Maggioni, et al., 2005). A greater weight gain at 6 months was found in patients taking pizotifen, amitriptyline, and propranolol. Other psychotropic drugs can cause weight gain, such as clozapine, alanzepine, and some antidepressants such as amitryptyline, mirtazapine, lithium, valproic acid, carbamazepine, topiramate, zonisamide, and and some serotonin inhibitors (Ness-Abramof and Apovian, 2005), as well as pregabalin (Hamandi and Sander, 2006) and other new antiepileptic drugs (Marken and Pies, 2006).

If a person with neuropathic pain has weight gain from gabapentin, what alternatives are there? Gabapentin is structurally related to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and readily crosses the blood brain barrier (Morris, 1999), affecting presynaptic calcium channels to influence neurotransmitter release (Cheng and Chiou, 2006). As an anti-epileptic drug, gabapentin is not particularly effective as a monotherapy but may be useful in combination with other drugs (Harden, et al., 2005). Gabapentin relieves neuropathic pain in some patients, but a recent literature review suggest that amitriptylline and carbemapazine may be more beneficial and cheaper (Cepeda and Farrar, 2006).

Pregabalin, a structural congener of gabapentin, is a new anti-convulsant that was provisionally approved by the US Food and Drug Administration in December 2004 for treating neuropathic pain (Guay, 2005). In doses of 50-200 mg three times a day, pregabalin was superior to placebo for treatment of diabetic peripheral neuropathy and postherpetic neuralgia (p<0.001 to p<0.049) in several clinical trials. Weight gain was seen in about 14% of the patients at the highest dose of 600 mg/day (Hamandi and Sander, 2006).

In summary, gabapentin seems to cause weight gain in a small proportion of patients. The weight gain appears to be more common with higher doses exceeding 3000 mg/day and longer term therapies of 6 months or longer. Many other drugs that may be useful for neuropathic pain also seem to induce weight gain in 8-10% of patients. It may, however, be worthwhile to try these other drugs.

For further discussion: http://carecure.org/forum/showthread.php?p=427349#post427349


References

1. Petrere JA and Anderson JA (1994). Developmental toxicity studies in mice, rats, and rabbits with the anticonvulsant gabapentin. Fundam Appl Toxicol 23: 585-9. The developmental toxicity of the anticonvulsant agent gabapentin was evaluated in mice, rats, and rabbits treated by gavage throughout organogenesis. Mice received 500, 1000, or 3000 mg/kg on gestation days (GD) 6-15 and rats and rabbits received 60, 300, or 1500 mg/kg on GD 6-15 (rats) or 6-18 (rabbits). Additional groups received an equivalent volume of the vehicle, 0.8% methylcellulose, or remained untreated. All dams were observed daily for clinical signs of toxicity. In mice, body weights and food consumption were recorded on GD 0, 6, 12, 15, and 18 while in rats and rabbits these parameters were evaluated daily. Near term (mouse, GD 18; rat, GD 20; and rabbit, GD 29) each female was euthanatized, necropsies were performed, and litter and fetal data were collected. Live fetuses were examined for external, visceral, and skeletal variations and malformations. No adverse maternal or fetal effects were observed in mice or rats given doses up to 1500 or 3000 mg/kg, respectively. No treatment-related maternal or fetal effects were apparent in rabbits given 60 or 300 mg/kg. At 1500 mg/kg, one rabbit died, four others aborted, and reduced food consumption and body weight gain were observed. No other reproductive, litter, or fetal parameters were affected, except that the incidence of visceral variations in rat fetuses was slightly but statistically significantly increased at 1500 mg/kg due to a slight increase in the incidence of dilated renal pelvis. This finding was not considered biologically significant because this degree of variability has been seen in this strain of rats.(ABSTRACT TRUNCATED AT 250 WORDS). Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, Michigan 48105. http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=7867910

2. Morris GL, 3rd (1995). Efficacy and tolerability of gabapentin in clinical practice. Clin Ther 17: 891-900. The efficacy and tolerability of gabapentin therapy for seizures in patients in clinical practice were retrospectively evaluated. Demographics, seizure type and history, prior anticonvulsant therapy, concomitant anticonvulsant medications, gabapentin dosing, side effects, seizure response, and tolerability data were obtained from 100 consecutive clinical practice patients (47 men and 53 women) treated with gabapentin. All patients had been previously treated with a mean of 2.9 anticonvulsant drugs and were currently taking a mean of 1.75 anticonvulsant drugs. Seventy-two patients experienced a greater than 50% reduction in seizures, and 23 of these patients experienced a greater than 75% reduction; 57 patients continued gabapentin treatment, 5 of whom remain seizure free and side effect free with gabapentin monotherapy. Of the 42 patients discontinuing treatment, 17 had no seizure reduction, 17 had side effects, and 8 had both. One additional patient died. The mean daily dosage for all 100 patients was 2107 mg, and the mean daily dosage for patients who continued gabapentin treatment was 2270 mg. No linear relationship was found between dosage and patient weight. Fifty-two patients had the dosage of at least 1 concomitant anticonvulsant medication reduced, 31 had at least 1 concomitant anticonvulsant medication removed from the regimen, and 9 required a dosage increase of at least 1 anticonvulsant medication. Twenty patients experienced fatigue, which was usually transient after treatment initiation; in 13 patients fatigue was associated with carbamazepine therapy. In addition, 7 patients experienced ataxia (6 of whom were taking concomitant carbamazepine), and 2 experienced weight gain. Patients experiencing side effects resulting in discontinuation were taking a mean daily dose of gabapentin of 1182 mg. The maximum effective and tolerable daily dosage under clinical practice conditions appears to exceed dosages established in clinical trials. The results of our study suggest broader treatment parameters for gabapentin than initially determined in the more restrictive clinical trials conducted during the drug's development. Department of Neurology, Medical College of Wisconsin, Milwaukee, USA. http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=8595641

3. Sigler RE, Gough AW and de la Iglesia FA (1995). Pancreatic acinar cell neoplasia in male Wistar rats following 2 years of gabapentin exposure. Toxicology 98: 73-82. Gabapentin, an anticonvulsant agent designated chemically as 1-(aminomethyl)-cyclohexaneacetic acid, was evaluated in a 2-year tumor bioassay in male Wistar rats. Three groups of 50 rats were fed gabapentin at 250, 1000 and 2000 mg/kg in the diet for 104 weeks. A fourth group was fed diet without drug. All rats were subjected to full histopathological evaluation. Body weight gain suppression occurred at 1000 and 2000 mg/kg. Survival was comparable across all groups. There was a treatment-related increase in the number of pancreatic acinar cell carcinomas; 0, 4, 3 and 8 of these carcinomas were observed in the control, 250, 1000 and 2000 mg/kg groups, respectively. There were no other increases in other tumor types, and there were no tumor increases in female rats. The frequency of pancreatic acinar cell hyperplasia was similar in treated and control groups. Biologically, the pancreatic carcinomas were not invasive, did not metastasize, were of late onset and did not compromise survival. Thus, gabapentin was a carcinogen in male Wistar rats. However, the tumorigenic response was of low-grade because it constituted a late tumor response which required very high doses. We reported recently that mice treated with gabapentin had no increase in pancreatic tumors. Therefore, neoplastic development was confined to the pancreas in a single sex and species of rodent. Consequently, gabapentin at therapeutic doses poses a low carcinogenic risk to humans. Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105, USA. http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=7740556

4. DeToledo JC, Toledo C, DeCerce J and Ramsay RE (1997). Changes in body weight with chronic, high-dose gabapentin therapy. Ther Drug Monit 19: 394-6. 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. Department of Neurology, University of Miami, FL 33136, USA. http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=9263379
5. Baulac M, Cavalcanti D, Semah F, Arzimanoglou A and Portal JJ (1998). Gabapentin add-on therapy with adaptable dosages in 610 patients with partial epilepsy: an open, observational study. The French Gabapentin Collaborative Group. Seizure 7: 55-62. The objectives were to evaluate gabapentin add-on therapy in a large population under conditions close to real practice and to determine the therapeutic doses as reached with adaptable dosages. A 6-month multicentre, open-label study, involved addition of gabapentin to pre-existing treatment at the initial dosage of 1200 mg and subsequent adjustment between 900 and 2400 mg/day according to efficacy and tolerability. A study group of 610 adult patients, with partial epilepsy, persistent seizures and a median seizure frequency with a baseline of 7.2 per month were recruited; one-third had less than four seizures per month. Polypharmacy was frequent, with a mean of 2.3 concomitant drugs. After 6 months, 368 patients (62%) continued on gabapentin, at a mean dosage of 1739 mg/day with 44% of responders. On an intention-to-treat basis, median reduction in frequency was 21.2%, and the responder rate was 33.9%. The responder rate increased to 40.7% in the less severe subgroup receiving only one concomitant drug. Seventy-nine patients (13.4%) remained without seizures during the last evaluation period, versus nine (1.5%) during the baseline. Most of them had initially less than four seizures per month. The most frequent adverse effects, somnolence (29.3%), asthenia (14.6%), nausea (7.9%), ataxia (7.7%) and vertigo (7.2%), occurred rapidly after initial titration to 1200 mg/day, and were usually transitory. Weight gain (8.8%) seemed to be related to gabapentin dose. The combination of two recent drugs, vigabatrin and gabapentin, in 190 patients led to similar efficacy levels, with a tendency for more frequent somnolence and asthenia. Epilepsy Unit, Hopital de la Pitie-Salpetriere, Paris, France. http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=9548227

6. Wilton LV and Shakir S (2002). A postmarketing surveillance study of gabapentin as add-on therapy for 3,100 patients in England. Epilepsia 43: 983-92. PURPOSE: Our aim was to monitor the use of gabapentin (GBP) by patients prescribed this drug by primary care physicians in England soon after it was marketed in the United Kingdom. METHODS: A noninterventional observational cohort study was conducted by using the technique of prescription-event monitoring. Patients were identified from dispensed National Health Service prescriptions. Outcome data were obtained from questionnaires sent to the doctor approximately 6 months after the initial prescription. These data included demographic information, events reported since starting GBP, and reason for stopping the drug, if it was stopped. Incidence rates were calculated for given periods for all events reported. Additional information was requested for selected events of medical interest, including pregnancies. Standardised mortality ratio (SMR) was calculated. RESULTS: The cohort comprised 3,100 patients, of whom 136 (4%) were children. The median duration of treatment was 8.1 months. The most frequently reported adverse events reported during the first month of treatment, drowsiness/sedation, dizziness, and malaise/lassitude, also were the commonest reasons for discontinuing GBP and reported as suspected adverse drug reactions (ADRs). There were no congenital anomalies in the 11 babies born to women who used GBP during the first trimester of pregnancy. Crude mortality rate was 5 times that in general population but similar to that in other published studies. CONCLUSIONS: Neurologic-related events were the most frequently reported adverse events. They also were the commonest reasons for discontinuing treatment and reported as suspected ADRs. No previously unrecognised adverse events were detected in this large cohort of patients who were among the first treated with gabapentin in England. Drug Safety Research Unit, Southampton, England. lynda.wilton@dsru.org http://www.ncbi.nlm.nih.gov/entrez/q..._uids=12199723

7. Maggioni F, Ruffatti S, Dainese F, Mainardi F and Zanchin G (2005). Weight variations in the prophylactic therapy of primary headaches: 6-month follow-up. J Headache Pain 6: 322-4. We conducted a study on 367 patients (86% female, 14% male; mean age 37+/-15 years) suffering from migraine with and without aura and chronic tension-type headache to evaluate the incidence of weight gain, an undesirable side effect observed during prophylactic therapy in primary headaches. Patients treated with amitriptyline (20 and 40 mg), pizotifen (1 mg), propranolol (80-160 mg), atenolol (50-100 mg), verapamil (160-240 mg), valproate (600 mg) and gabapentin (900-1200 mg) were evaluated after a period of 3 and 6 months. In particular, 89 patients were assessed (78% female, 22% male) at 6 months, of whom 10 were in treatment with amitriptyline 20 mg, 19 with amitriptyline 40 mg, 7 with pizotifen (1 mg), 13 with propranolol (80-160 mg), 4 with verapamil (160 mg), 10 with valproate (600 mg), 15 with atenolol (50 mg) and 11 with gabapentin (900-1200 mg). The control group consisted of 97 patients with migraine (79% female, 21% male; mean age 35+/-16 years) without indication for prophylactic therapy. Weight variations >or=1 kg were considered. After 6 months of therapy, the percentage of patients with weight gain was 86% with pizotifen (6/7; mean weight increase 4.4+/-2.5 kg), 60% with amitriptyline 20 mg (6/10; 3.1+/-1.6), 47% with amitriptyline 40 mg (9/19; 5.4+/-2.7), 25% with valproate 600 mg (2/8, 3.0+/-2.8 kg), 25% with verapamil (1/4, 2.5 kg), 20% with atenolol (3/15, 1.7+/-0.6 kg), 9% with gabapentin (1/11, 1.5 kg) and 8% with propranolol (1/13; 6 kg). We conclude that propranolol, gabapentin, atenolol, verapamil and valproate affect body weight in a modest percentage of patients at 6 months. A greater mean weight gain at 6 months was found in patients treated with pizotifen, amitriptyline, and, in one patient out of 13, with propranolol. Headache Centre, Department of Neurosciences, University of Padua, Via Giustiniani 3, I-35128, Padua, Italy. ferdinando.maggioni@unipd.it http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16362700

8. Ness-Abramof R and Apovian CM (2005). Drug-induced weight gain. Timely Top Med Cardiovasc Dis 9: E31. Drug-induced weight gain is a serious side effect of many commonly used drugs leading to noncompliance with therapy and to exacerbation of comorbid conditions related to obesity. Improved glycemic control achieved by insulin, insulin secretagogues or thiazolidinedione therapy is generally accompanied by weight gain. It is a problematic side effect of therapy due to the known deleterious effect of weight gain on glucose control, increased blood pressure and worsening lipid profile. Weight gain may be lessened or prevented by adherence to diet and exercise or combination therapy with metformin. Weight gain is also common in psychotropic therapy. The atypical antipsychotic drugs (clozapine, olanzepine, risperidone and quetiapine) are known to cause marked weight gain. Antidepressants such as amitriptyline, mirtazapine and some serotonin reuptake inhibitors (SSRIs) also may promote appreciable weight gain that cannot be explained solely by improvement in depressive symptoms. The same phenomenon is observed with mood stabilizers such as lithium, valproic acid and carbamazepine. Antiepileptic drugs (AEDs) that promote weight gain include valproate, carbamazepine and gabapentin. Lamotrigine is an AED that is weight-neutral, while topiramate and zonisamide may induce weight loss. Endocrine Unit, Sapir Medical Center, Tel Aviv University, Israel. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16341287

9. Hamandi K and Sander JW (2006). Pregabalin: a new antiepileptic drug for refractory epilepsy. Seizure 15: 73-8. Pregabalin is a recently licensed and marketed antiepileptic drug for use as adjunctive treatment of partial epilepsy. It acts at presynaptic calcium channels, modulating neurotransmitter release in the CNS, properties it shares with gabapentin. Its clinical development over the past decade has included its use in the treatment of neuropathic pain, and generalized anxiety disorder, in addition to epilepsy. Three multi-centre randomised, double-blind, placebo-controlled trials enrolling patients with refractory partial epilepsy have demonstrated an antiepileptic effect of pregabalin against placebo, as adjunctive therapy, with 31-51% of patients showing a 50% reduction in seizure frequency. Adverse effects were dose related, the commonest being somnolence, dizziness, and ataxia. Weight gain was seen in 14% of patients on the highest dose of 600 mg/day. Around 9000 people have been exposed to pregabalin in its development for all indications. No idiosyncratic reactions have been described to date. Pregabalin may be a useful addition in the treatment of refractory partial epilepsy. As with all new AEDs long-term follow up and post marketing surveillance is required. Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16413993

10. Marken PA and Pies RW (2006). Emerging treatments for bipolar disorder: safety and adverse effect profiles. Ann Pharmacother 40: 276-85. OBJECTIVE: To provide an overview of the safety and tolerability of newer agents used to treat bipolar disorder (BPD) and provide clinicians with management strategies for drug-related toxicity and adverse effects. DATA SOURCES: MEDLINE was searched through July 2005 for BPD treatment, adverse effects, tolerability, safety, emerging agents, atypical antipsychotics, new antiepileptic drugs (AEDs), risperidone, quetiapine, clozapine, ziprasidone, aripiprazole, lamotrigine, topiramate, gabapentin, oxcarbazepine, and olanzapine. STUDY SELECTION AND DATA EXTRACTION: Results from randomized controlled trials, open-label studies, and reviews are described. DATA SYNTHESIS: Emerging agents recently approved for BPD include atypical antipsychotics and new AEDs. Safety and tolerability are as important as efficacy because poor adherence in BPD worsens outcome; metabolic and other comorbidities pose specific challenges; and manic patients often require combination therapy, which increases adverse effects. Most atypical antipsychotics cause fewer extrapyramidal symptoms than conventional antipsychotics, but may cause more weight gain and metabolic complications. The newer AEDs generally cause less weight gain than the older agents, and some even promote weight loss. Several newer AEDs used in BPD also offer the advantages of fewer drug interactions and less need for therapeutic drug monitoring compared with older AEDs. CONCLUSIONS: Pending the results of ongoing controlled studies, several emerging agents may be useful additions to the therapeutic arsenal for BPD. Division of Pharmacy Practice; Professor of Psychiatry, Schools of Pharmacy and Medicine, University of Missouri-Kansas City, Kansas City, MO. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16403851

11. Morris GL (1999). Gabapentin. Epilepsia 40 Suppl 5: S63-70. Gabapentin (GBP) is a antiepileptic drug (AED) indicated as adjunct therapy for treatment of partial seizures, with and without secondary generalization, in patients 12 and older with epilepsy. GBP (1-(aminomethyl) cyclohexaneacetic acid) is structurally related to gamma-aminobutyric acid (GABA), which readily crosses the blood-brain barrier. Radiolabeled GBP binds throughout the central nervous system in anatomic areas important in treatment of seizures. Its precise mechanism of action is unknown. An open-label, dose-ranging study of doses up to 1,800 mg produced > or =50% seizure reductions [responder rate (RR)] in 29% of patients with partial seizures. Three double-blind, placebo-controlled, parallel add-on trials at doses of 300-1,800 mg have produced RR of up to 28%, with a placebo RR of 8-10%. An active controlled, parallel group comparison of 600 mg to 2,400 mg in monotherapy conversion design showed no significant difference among the 600 mg, 1,200 mg, and 2,400 mg groups compared to a placebo group. An inpatient, active-controlled comparison of 300 mg and 3,600 mg in a parallel-design monotherapy trial showed that time to exit from the study was significantly longer for the 3,600-mg group and the completion rate significantly higher (53% vs. 17%) for patients receiving 3,600 mg/day vs. 300 mg/day of GBP. Successful double-blind, placebo-controlled trials in refractory childhood partial seizures and benign childhood epilepsy with centrotemporal spikes have been recently concluded. Absence was not successfully treated in one small double-blind trial. Open-label reports emphasize adjustments of patients to higher doses than those indicated in the package labeling. An open-label trial of GBP therapy in patients with partial seizures (n = 2,216) produced progressively greater seizure freedom rates as patients were titrated from > or =900 mg daily to > or = 1,800 mg daily (15.1% vs. 33.4%), with a similar effect on RR (18.1% vs. 44.9%). An add-on, open-label study treating partial seizures (n = 141) reported an RR of 71%, with 46% seizure-free in the last 8 weeks of treatment and doses up to 2,400 mg daily. A comparison trial of three doses of GBP to 600 mg of carbamazepine showed similar retention rates for 1,800 mg of GBP and 600 mg of CBZ. Another study reported 48% of patients experiencing 50% reduction, nine of whom had doses greater than 2,400 mg. Treatment in children has reported a 34.4% RR in 32 children with refractory partial seizures. A French open-label adjunctive trial documented a 33.9% RR; 13.4% were seizure-free during the evaluation period. Adverse experiences most commonly noted included somnolence, dizziness, and ataxia. Weight gain was sometimes reported with higher doses of GBP, and pediatric reports cite prominent behavioral changes, including hyperactivity, irritability, and agitation. GBP appears best used at doses at and potentially above those suggested in its package labeling. Although efficacy occurs at lower levels, increased GBP doses are associated with additional efficacy. Reports suggest that initiation at 2,400 mg or 3,600 mg may not be associated with increased adverse experiences. Titration to 900 or 1,200 mg on the first day of GBP therapy appear to be well tolerated. Department of Neurology, Medical College of Wisconsin, Milwaukee, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=10530696

12. Cheng JK and Chiou LC (2006). Mechanisms of the Antinociceptive Action of Gabapentin. J Pharmacol Sci Gabapentin, a gamma-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABA(B) receptors consisting of GABA(B1a) and GABA(B2) subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-alpha-amino acid transporter, activating ATP-sensitive K(+) channels, activating hyperpolarization-activated cation channels, and modulating Ca(2+) current by selectively binding to the specific binding site of [(3)H]gabapentin, the alpha(2)delta subunit of voltage-dependent Ca(2+) channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the alpha(2)delta subunit of spinal N-type Ca(2+) channels is very likely the analgesic action target of gabapentin. Institute, College of Medicine, National Taiwan University, Taiwan. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16474201

13. Harden CL, Kanner AM, Bautista JF and Brown TR (2005). Treatment-refractory epilepsy: an evidence-based approach to antiepileptic monotherapy. CNS Spectr 10: 1-13. Treatment options for epilepsy have increased in the last decade with the introduction of several new antiepileptic drugs (AEDs). As drug selection becomes more challenging, the use of evidence-based guidelines to aid in treatment decisions has become increasingly valued. The American Academy of Neurology's (AAN) guidelines for the use of new AEDs in refractory epilepsy offers many benefits, including expert panel recommendations based on clinically relevant questions with evidence-based responses. However, lack of evidence from randomized-controlled trials, particularly as they relate to monotherapy, limits the recommendations and their use in practice. The studies of new AEDs as monotherapy in treatment-refractory epilepsy are difficult to incorporate into clinical use because they are driven by Food and Drug Administration requirements to show superiority over placebo or pseudoplacebo (ie, low dose of active drug) rather than by clinical questions. However, based on Class I evidence, the AAN guidelines have granted Level A recommendations (established effectiveness) for oxcarbazepine and topiramate monotherapy, and a Level B recommendation (probable effectiveness) for lamotrigine monotherapy in the use of refractory partial epilepsy. There is insufficient evidence to recommend gabapentin, levetiracetam, tiagabine, or zonisamide monotherapy. No monotherapy AED trials have been conducted in refractory generalized epilepsy. Because no differences in efficacy have been reported for AEDs as initial therapy of partial seizures, differences in adverse events, such as weight gain, tremor, and hair loss, are key in drug selection. More comparative studies between the AEDs are necessary for both monotherapy and add-on therapy for treatment-refactory epilepsy. Comprehensive Epilepsy Center, Weill College of Cornell University, New York, NY, USA. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=15744225

14. Cepeda MS and Farrar JT (2006). Economic evaluation of oral treatments for neuropathic pain. J Pain 7: 119-28. The effectiveness of amitriptyline, carbamazepine, gabapentin, and tramadol for the treatment of neuropathic pain has been demonstrated, but it is unknown which one is the most cost-effective. We designed a cost-utility analysis of a hypothetical cohort with neuropathic pain of postherpetic or diabetic origin. The perspective of the economic evaluation was that of a third-party payor. For effectiveness and safety estimates, we performed a systematic review of the literature. For direct cost estimates, we used average wholesale prices, and the American Medicare and Clinical Laboratory Fee Schedules. For utilities of health states, we used the Health Utilities Index. We modeled 1 month of therapy. For comparisons among treatments, we estimated incremental cost per utility gained. To allow for uncertainty from variations in drug effectiveness, safety, and amount of medication needed, we conducted a probabilistic Monte Carlo simulation. Amitriptyline was the cheapest strategy, followed by carbamazepine, and both were equally beneficial. Gabapentin was the most expensive as well as the least beneficial. A multivariable probabilistic simulation produced similar results to the base-case scenario. In summary, amitriptyline and carbamazepine are more cost-effective than tramadol and gabapentin and should be considered as first-line treatment for neuropathic pain in patients free of renal or cardiovascular disease. PERSPECTIVE: Prescription practices should be based on the best available evidence, which includes the evaluation of the medication's cost-effectiveness. This does not mean that the cheapest or the most expensive, but rather the most cost-effective medication should be chosen-the one whose benefits are worth the harms and costs. We report a cost-effectiveness evaluation of treatments for neuropathic pain. Department of Anesthesia and Clinical Epidemiology Unit, Javeriana University School of Medicine, Bogota, Colombia. http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16459277

15. Guay DR (2005). Pregabalin in neuropathic pain: a more "pharmaceutically elegant" gabapentin? Am J Geriatr Pharmacother 3: 274-87. OBJECTIVE: This article reviews the available information on pregabalin, a new anticonvulsant for peripheral neuropathic pain. Pregabalin was provisionally approved by the US Food and Drug Administration in December 2004 and was granted final approval after controlled substance scheduling (Schedule V) by the US Drug Enforcement Agency in August 2005. METHODS: A MEDLINE search (1986-August 2005) was conducted to identify pertinent studies in the English language. The search terms included pregabalin, PD144723, CI-1008, gabapentin, and neuropathic pain. Additional references were obtained from the bibliographies of identified articles. All studies that evaluated any aspect of pregabalin in vitro or in vivo in animals or humans were included, with a focus on data relevant to older adults. RESULTS: In preclinical studies, pregabalin, a structural congener of gabapentin, exhibited antinociceptive activity in animal models of neuropathic and inflammatory pain. Unlike gabapentin, pregabalin was well absorbed (> 90%), and its absorption was dose independent. Like gabapentin, pregabalin was predominantly excreted unchanged in the urine (> or = 98%). Dosed at 50 to 200 mg TID, pregabalin was superior to placebo in relieving pain and improving sleep and health-related quality of life in patients with diabetic peripheral neuropathy and postherpetic neuralgia (P < 0.001-P < 0.049). No active-controlled trials were available. The most problematic adverse events associated with pregabalin were dizziness and somnolence (21%-26%). CONCLUSIONS: In the absence of active-controlled clinical trials and geriatric-specific efficacy/tolerability data, the place of pregabalin in the analgesic armamentarium for the elderly is unclear. Because pregabalin is a Schedule V controlled substance, its utility is not compromised by substantial limitation of access or the need for extra steps in prescribing. However, abuse potential is a consideration, and utilization should be carefully monitored, particularly in patients with a past or current history of substance abuse. The improved pharmacokinetic profile of pregabalin relative to gabapentin is manifested in linear and dose-independent absorption and a narrow therapeutic dosing range. However, pregabalin still requires multiple administrations per day, and daily doses > 150 mg/d require dose titration. The relatively high frequency of central nervous system adverse events, particularly dizziness and somnolence, is a concern in the elderly. Time and further experience should clarify the role of this agent. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA. guayx001@umn.edu http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16503325

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