Clonidine, gabapentin, and some SSRIs effective for hot flashes.
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Further evidence for the role of the alpha(2)delta subunit of voltage dependent calcium channels in models of neuropathic pain.
1. Current analgesic therapy is dominated by NSAIDs and opiates, however these agents have limited efficacy in the treatment of neuropathic pain. The novel anticonvulsant agent gabapentin (Neurontin) has been shown to be an effective treatment for neuropathic pain in the clinic. Recent studies have demonstrated that gabapentin selectively interacts with the alpha(2)delta subunit of voltage dependent calcium channels (VDCCs) which may be important in its mechanism of action. 2. Previous studies have identified a gabapentin analogue, 3-methyl gabapentin, that stereoselectively interacts with the alpha(2)delta subunit of VDCCs. Thus, whilst (1S, 3R) 3-methyl gabapentin binds to the alpha(2)delta protein with high affinity (IC(50)=42 nM), the corresponding (1R,3R) isomer is 300 times weaker (Bryans et al., 1998: J. Med. Chem., 41, 1838 - 1845). The present study examines the activity of diastereoisomers of 3-methyl gabapentin in two rat models of neuropathic pain to assess the importance of an interaction with the alpha(2)delta subunit of VDCCs. 3. (1S,3R) 3-methyl-gabapentin dose-dependently (10 - 100 mg kg(-1), p.o.) blocked the maintenance of static allodynia in the rat streptozocin and Chung models of neuropathic pain with MEDs of 30 mg kg(-1). This isomer also dose-dependently blocked the maintenance of dynamic allodynia in both models with respective MEDs of 30 and 100 mg kg(-1). In contrast, (1R,3R) 3-methyl gabapentin (100 mg kg(-1), p.o.) failed to block either static or dynamic allodynia in the streptozocin model. 4. It is concluded that these data further support the hypothesis that the alpha(2)delta subunit of VDCCs plays an important role in the maintenance of mechanical hypersensitivity in models of neuropathic pain.
Acetates↗
Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans.
Abnormal processing of somatosensory inputs in the central nervous system (central sensitization) is the mechanism accounting for the enhanced pain sensitivity in the skin surrounding tissue injury (secondary hyperalgesia). Secondary hyperalgesia shares clinical characteristics with neurogenic hyperalgesia in patients with neuropathic pain. Abnormal brain responses to somatosensory stimuli have been found in patients with hyperalgesia as well as in normal subjects during experimental central sensitization. The aim of this study was to assess the effects of gabapentin, a drug effective in neuropathic pain patients, on brain processing of nociceptive information in normal and central sensitization states. Using functional magnetic resonance imaging (fMRI) in normal volunteers, we studied the gabapentin-induced modulation of brain activity in response to nociceptive mechanical stimulation of normal skin and capsaicin-induced secondary hyperalgesia. The dose of gabapentin was 1,800 mg per os, in a single administration. We found that (i) gabapentin reduced the activations in the bilateral operculoinsular cortex, independently of the presence of central sensitization; (ii) gabapentin reduced the activation in the brainstem, only during central sensitization; (iii) gabapentin suppressed stimulus-induced deactivations, only during central sensitization; this effect was more robust than the effect on brain activation. The observed drug-induced effects were not due to changes in the baseline fMRI signal. These findings indicate that gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.
Adult↗
The safety and effectiveness of newer antiepileptics: a comparative postmarketing cohort study.
Clinical trials for the newer antiepileptic drugs (AEDs) have provided inconclusive information to evaluate comparative risk benefit. The authors use data from postmarketing observational cohort studies to compare the failure of treatment with lamotrigine, vigabatrin, and gabapentin in patients with refractory epilepsy. The Drug Safety Research Unit has conducted prescription event monitoring (PEM) studies for lamotrigine, vigabatrin, and gabapentin to monitor their safety when used in primary care. The primary outcome of this study was time to treatment failure in patients who had been prescribed the drug after the start of the PEM study. Patients on gabapentin had reduced time to treatment failure compared to those on the other 2 drugs. The age- and sex-adjusted hazard ratio of failure was 1.53 (95% confidence interval [CI] = 1.38-1.70) for gabapentin compared to lamotrigine and 1.19 (95% CI = 1.10-1.30) for vigabatrin compared to lamotrigine. The observed differences between the 3 study drugs might be confounded by a higher proportion of patients treated with gabapentin having refractory epilepsy, a shorter duration of the gabapentin PEM study, and a lower relative dose of gabapentin (approved at the time of the PEM study). The current study provides information about the routine usage of newer AEDs, which complements evidence from clinical trials regarding the efficacy and safety of these AEDs. Although this study showed differences on times to treatment failure between lamotrigine, vigabatrin, and gabapentin, the results are only useful when considered together with results from other studies seeking to answer the same questions.
Adolescent↗
Cost-effectiveness of pregabalin for the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia: a Canadian perspective.
BACKGROUND: Neuropathic pain (NeP) is a chronic condition that occurs frequently with diabetes and herpes zoster infection. In addition to potentially lasting many years, the relationship between chronic pain, anxiety/depression, and sleep, also referred to as the triad of pain, causes functional impairment in many areas of life. OBJECTIVE: The aim of this study was to examine the 12-week cost-effectiveness of 2 treatments of NeP, pregabalin versus gabapentin, in managing diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN) in a Canadian setting. METHODS: A stochastic simulation model evaluating NeP treatment was adapted to the Canadian setting. Using data from clinical trials of pregabalin (150-600 mg/d) and gabapentin (900-3600 mg/d), the model simulated 12-week treatment outcomes for patients with DPN or PHN. Resource utilization was identified through an Internet-based survey among 80 Canadian physicians. Utility values (as measured using the EuroQol EQ-5D) were obtained from 126 NeP patients participating in a cross-sectional study conducted at Canadian primary care sites. The economic analysis was expressed as incremental cost per quality-adjusted life year (QALY) gained and as incremental cost per day with no or mild pain. Model sensitivity to changes in key parameters was assessed. RESULTS: Following 12-week treatment, compared with gabapentin, pregabalin was projected to result in 6 and 9 additional days with no or mild pain for patients with DPN and PHN, respectively. Pregabalin therapy was estimated to provide an additional 0.0047 QALY and 0.0086 QALY over gabapentin administration, for DPN and PHN, respectively. Mean (SE) direct costs per DPN patient were estimated as 837.53 Can dollars (37.31 dollars) (2004 dollars) with gabapentin and 818.49 dollars (36.50 dollars) with pregabalin, and per PHN patient as 720.61 dollars (33.70 dollars) with gabapentin and 667.07 dollars (25.33 dollars) with pregabalin. Model findings were sensitive to variation in the dose and corresponding cost of the comparator, but not in other parameters. CONCLUSION: Based on the results of this analysis, in the treatment of NeP associated with DPN or PHN, pregabalin was a dominant or cost-effective treatment strategy compared with gabapentin.
Amines↗
3-substituted GABA analogs with central nervous system activity: a review.
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.
Acetates↗
Changes in expression of voltage-dependent ion channel subunits in dorsal root ganglia of rats with radicular injury and pain.
STUDY DESIGN: Changes in expression of voltage-dependent ion channel subunits were examined in the radicular pain state. Furthermore, antinociceptive effects of gabapentin on radicular pain were compared with effects on peripheral neuropathic pain. OBJECTIVES: To clarify molecular substrates involved in the development of radicular pain, and to investigate the responsiveness of radicular pain to gabapentin. SUMMARY OF BACKGROUND DATA: Peripheral nerve injuries are known to induce dynamic changes of voltage-dependent Na+ and Ca2+ channel subunits expression in dorsal root ganglion neurons. However, the expression profiles of Na+ and Ca2+ channel subunits in the radicular pain state have not been examined. METHODS: Two radicular pain models and one peripheral neuropathic pain model were prepared. By using semiquantitative reverse transcriptase-polymerase chain reaction, the expression levels of several Na+ and Ca2+ channel subunits in the dorsal root ganglions of these pain model rats were investigated. The antinociceptive effects of gabapentin were examined in a behavioral study using the aforementioned pain models. RESULTS: All three neuropathic pain operations induced comparable mechanical allodynia and thermal hyperalgesia. The upregulation of the Na(v)1.3 Na+ channel and Ca(v)alpha2delta Ca2+ channel subunits was observed only in the peripheral nerve injury model. A downregulation of the Na(v)1.9 channel was observed in all three pain model rats. A lower dose of gabapentin was significantly more effective in alleviating the mechanical allodynia of rats with radicular pain. CONCLUSIONS: The reduction of Na(v)1.9 found in all three models may link to the neuropathic pain state, including radicular pain. The lower sensitivity to gabapentin in rats with peripheral neuropathic pain might be partly explained by the marked upregulation of Ca(v)alpha2delta in the dorsal root ganglions, suggesting that gabapentin may be more effective in radicular pain treatment.
Acetates↗
Antinociceptive activity of the N-methyl-D-aspartate receptor antagonist N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain.
N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) is a novel low-affinity, noncompetitive N-methyl-d-aspartate receptor antagonist. The current study compared the antinociceptive effects of CHF3381 with those of gabapentin and memantine in in vitro and in vivo models of pain. In isolated rat spinal cord, CHF3381 and memantine, but not gabapentin, produced similar inhibition of the wind-up phenomenon. CHF3381 suppressed the maintenance of carrageenan-induced thermal and mechanical hyperalgesia in the rat with a minimum significantly effective dose (MED) of 30 mg/kg p.o. Memantine produced a partial reversal of both thermal and mechanical hyperalgesia (MED = 10 and 15 mg/kg i.p., respectively). Gabapentin reversed mechanical hyperalgesia (MED = 10 mg/kg s.c.), but did not affect thermal hyperalgesia. In the mouse formalin test, CHF3381 and memantine preferentially inhibited the late phase (MED = 30 and 20 mg/kg i.p., respectively); gabapentin inhibited only the late phase (MED = 30 mg/kg s.c.). Unlike morphine, CHF3381 chronic administration was not accompanied by the development of tolerance in the formalin test. Furthermore, morphine tolerance did not cross-generalize to CHF3381. In rats with a sciatic nerve injury, CHF3381 relieved both cold and mechanical allodynia (MED = 100 mg/kg p.o.). In contrast, memantine was inactive. Gabapentin blocked cold allodynia (MED = 30 mg/kg s.c.), but had marginal effects on mechanical allodynia. In diabetic neuropathy, CHF3381 reversed mechanical hyperalgesia (MED = 50 mg/kg p.o.). Memantine (15 mg/kg i.p.) produced an antinociceptive effect, whereas gabapentin (100 mg/kg p.o.) had no significant effect. Thus, CHF3381 may be useful for the therapy of peripheral painful neuropathies.
Animals↗
Anticonvulsant drugs for acute and chronic pain.
BACKGROUND: Anticonvulsant drugs have been used in the management of pain since the 1960s. The clinical impression is that they are useful for chronic neuropathic pain, especially when the pain is lancinating or burning. Readers are referred to reviews of carbamazepine and gabapentin in the Cochrane Library which replace the information on those drugs in this review. Other drugs remain unchanged at present in this review OBJECTIVES: To evaluate the analgesic effectiveness and adverse effects of anticonvulsant drugs for pain management in clinical practice . Migraine and headache studies are excluded in this revision. SEARCH STRATEGY: Randomised trials of anticonvulsants in acute, chronic or cancer pain were identified by MEDLINE (1966-1999), EMBASE (1994-1999), SIGLE (1980-1999) and the Cochrane Controlled Trials Register (CENTRAL/CCTR) (Cochrane Library Issue 3, 1999). In addition, 41 medical journals were hand searched. Additional reports were identified from the reference list of the retrieved papers, and by contacting investigators. Date of most recent search: September 1999. SELECTION CRITERIA: Randomised trials reporting the analgesic effects of anticonvulsant drugs in patients, with subjective pain assessment as either the primary or a secondary outcome. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Numbers-needed-to-treat (NNTs) were calculated from dichotomous data for effectiveness, adverse effects and drug-related study withdrawal, for individual studies and for pooled data. MAIN RESULTS: Twenty-three trials of six anticonvulsants were considered eligible (1,074 patients). The only placebo-controlled study in acute pain found no analgesic effect of sodium valproate. Three placebo-controlled studies of carbamazepine in trigeminal neuralgia had a combined NNT (95% confidence interval (CI)) for effectiveness of 2.5 (CI 2.0-3.4). A single placebo-controlled trial of gabapentin in post-herpetic neuralgia had an NNT of 3.2 (CI 2.4-5.0). For diabetic neuropathy NNTs for effectiveness were as follows: (one RCT for each drug) carbamazepine 2.3 (CI 1.6-3.8), gabapentin 3.8 (CI 2.4-8.7) and phenytoin 2.1 (CI 1.5-3.6).Numbers-needed-to-harm (NNHs) were calculated where possible by combining studies for each drug entity irrespective of the condition treated. The results were, for minor harm, carbamazepine 3.7 (CI 2.4-7.8), gabapentin 2.5 (CI 2.0-3.2), phenytoin 3.2 (CI 2.1-6.3). NNHs for major harm were not statistically significant for any drug compared with placebo. Phenytoin had no effect in irritable bowel syndrome, and carbamazepine little effect in post-stroke pain. Clonazepam was effective in one study of temporomandibular joint dysfunction. AUTHORS' CONCLUSIONS: Although anticonvulsants are used widely in chronic pain surprisingly few trials show analgesic effectiveness. Only one studied considered cancer pain. There is no evidence that anticonvulsants are effective for acute pain. In chronic pain syndromes other than trigeminal neuralgia, anticonvulsants should be withheld until other interventions have been tried. While gabapentin is increasingly being used for neuropathic pain the evidence would suggest that it is not superior to carbamazepine.
Acute Disease↗
Antiepileptic drugs in migraine prevention.
Migraineurs may continue to experience attacks, despite daily use of one or more agents from a wide range of drugs, including beta-blockers, calcium channel blockers, serotonin antagonists, tricyclic antidepressants, monoamine oxidase inhibitors, and antiepileptic agents. Divalproex sodium is the only antiepileptic drug approved for migraine prevention. Gabapentin, topiramate, and other antiepileptic agents are being evaluated for migraine prevention and treatment. Prospective, double-blind, placebo-controlled clinical trials of divalproex, gabapentin, and topiramate for migraine prevention generally were composed of a prospective baseline period, a dose titration period, and a fixed-dose treatment period. The primary efficacy variable was a reduction in the 28-day frequency of migraine headache. Patients receiving divalproex for 12 weeks at doses up to 1500 mg/day achieved significant decreases in the migraine frequency (P<.05), corresponding to reductions of 30% to 40% compared with baseline. Nearly half of the divalproex-treated patients had a 50% or more reduction from baseline in headache frequencies (P< or =.05). Asthenia, vomiting, somnolence, tremor, and alopecia were common adverse events associated with divalproex. Significant reductions in migraine frequency were also observed with gabapentin (1800 to 2400 mg/day) when compared with placebo (P<.01), and nearly half of all patients treated at the highest dose experienced a reduction in headache rate of 50% or more. Somnolence was the most commonly reported adverse event among the gabapentin-treated patients. Two single-center, double-blind, placebo-controlled clinical trials evaluated topiramate for migraine prevention. A lower 28-day migraine frequency was seen during 18 weeks of administration at a maximum daily dose of 200 mg (P =.09). In a second study, a significantly lower mean 28-day migraine frequency was observed during 16 weeks of treatment with topiramate (P =.0015). Mean reduction in migraine frequency was also significantly greater in topiramate-treated patients (P =.0037). Paresthesias, diarrhea, somnolence, and altered taste were commonly reported adverse events in the topiramate-treated patients. Unlike some patients given divalproex or gabapentin, some given topiramate reported weight loss. Large, double-blind, placebo-controlled trials may prove the effectiveness of novel antiepileptic drugs in migraine prevention.
Acetates↗
Differential effects of neuropathic analgesics on wind-up-like pain and somatosensory function in healthy volunteers.
OBJECTIVES: To investigate the effects of gabapentin, carbamazepine, and amitriptyline on temporal summation, simple nociceptive pain, and innocuous touch sensation in healthy volunteers. METHODS: A placebo controlled four-way crossover double-blind randomized protocol was followed. Seventeen healthy subjects, male and female, aged 18 to 24, took part. Punctate pain, temporal summation pain to repeat punctate stimulation, and vibration detection threshold were assessed in triplicate. Study drugs were given as bedtime and early morning doses with assessments carried out midmorning. RESULTS: Gabapentin and carbamazepine significantly reduced the intensity of temporal summation pain (P < 0.001 and P < 0.01 respectively), whereas amitriptyline significantly increased temporal summation pain (P < 0.001). None of the drugs affected pain produced by a single punctate stimulus (P > 0.05). Carbamazepine increased vibration detection thresholds (P < 0.05), but neither gabapentin nor amitriptyline had any detectable effect on vibration. DISCUSSION: We have shown that gabapentin, carbamazepine, and amitriptyline, three pharmacologically different drugs, have distinct and quantifiable effects on somatosensory pathways in healthy volunteers. These findings provide a link between pharmacology of the study drugs and clinical effectiveness. The effects of gabapentin and carbamazepine on temporal summation pain show that these drugs can block centrally amplified wind-up pain in the absence of a neuropathic disorder.
Adolescent↗
The effects of diacerhein on mechanical allodynia in inflammatory and neuropathic models of nociception in mice.
In this study we analyzed the systemic antiallodynic properties of diacerhein, a drug used to treat osteoarthritis, in inflammatory and neuropathic models of nociception in mice. The effects of diacerhein were compared with those of gabapentin, a drug used clinically for the management of neuropathic pain. Similar to gabapentin, diacerhein was able to significantly reverse the mechanical allodynia induced by carrageenan. A significant inhibition of carrageenan-induced nociception was also observed when diacerhein was administered by the intrathecal but not by the intraplantar route. The treatment with diacerhein or with gabapentin also inhibited the mechanical allodynia induced by complete Freund's adjuvant (CFA) or after the partial ligation of the sciatic nerve (PLSN). In the same range of doses, diacerhein or gabapentin did not affect the locomotor activity, motor coordination, or body temperature of the animals. The present results indicate that diacerhein produces marked antiallodynic effects in carrageenan and CFA nociception models and also inhibits the neuropathic pain after PLSN, with an efficacy similar to that observed for gabapentin. Diacerhein may be a potentially interesting tool for the management of inflammatory and neuropathic pain.
Amines↗
Comparative pharmacokinetics of the newer antiepileptic drugs.
During the past few years a major increase has taken place in the number of drugs which have become available in the antiepileptic arsenal. In fact, 3 new antiepileptic drugs, vigabatrin, oxcarbazepine and lamotrigine, were recently approved in several European countries. Two other drugs, felbamate and gabapentin, are expected to be approved in the US in the near future. This review comparatively evaluates the pharmacokinetics of the following 10 new antiepileptic drugs: felbamate, flunarizine, gabapentin, lamotrigine, oxcarbazepine, remacemide, stiripentol, tiagabine, topiramate and vigabatrin. Three of the new drugs, gabapentin, topiramate and vigabatrin, are more promising on the basis of their pharmacokinetic features. They are well absorbed, excreted mainly unchanged in the urine, and are not susceptible to enzyme induction or inhibition. Their drug interaction potential appears to be minimal. About 50% of felbamate is excreted unchanged, with the rest eliminated by metabolism. The remaining drugs are eliminated by metabolic processes such as glucuronidation (lamotrigine), deglycine formation (remacemide) or oxidative metabolism (flunarizine and stiripentol). Oxcarbazepine and remacemide have high hepatic clearance and are biotransformed to hydroxy and deglycine metabolites, respectively, with the activity of their metabolites contributing to the antiepileptic activity of the parent drug after oral administration, despite high first-pass effect metabolism. Gabapentin and oxcarbazepine do not behave pharmacokinetically as their original design intended. Gabapentin is not effective as a chemical drug delivery system for gamma-aminobutyric acid (GABA), and oxcarbazepine serves as a prodrug to its hydroxy metabolite, but does not act as a drug on its own. Nevertheless, these 2 agents demonstrate efficacy in extensive preclinical and clinical trials. Although the pharmacokinetics features of these drugs are important, these features are secondary to their pharmacodynamic properties--i.e. to the requirement that new antiepileptic drugs have to have proven clinical efficacy and safety in epileptic patients.
Acetamides↗
Effects of new anticonvulsant medications on porphyrin synthesis in cultured liver cells: potential implications for patients with acute porphyria.
Some patients with acute hereditary porphyrias have seizures and require anticonvulsant therapy, but many anticonvulsants induce exacerbations of the hepatic porphyrias. Recently, several new anticonvulsants have become available. Among these are gabapentin, vigabatrin, felbamate, lamotrigine, and tiagabine. Little is known about their potential for induction of porphyric attacks. We used a cell culture model of primary chicken embryo liver cells, which maintain intact heme synthesis and regulation, to study the effects of these new anticonvulsants on porphyrin accumulation. Treatment of the cells with deferoxamine (250 microM) led to a partial block in heme synthesis, simulating the conditions encountered in human beings with porphyria. Concomitant exposure of these cells to phenobarbital (2 mM) strongly induced accumulation of porphyrins, serving as a positive control in this model. Cells were treated for 20 hours with increasing doses (3.2 to 1,000 microM) of the newer anticonvulsants, with or without deferoxamine. For most of these anticonvulsants 5 to 100 microM is representative of the concentrations achieved in humans with therapeutic doses. Porphyrins were measured spectrofluorometrically as uro-, copro-, and protoporphyrins. Results were confirmed by high-pressure liquid chromatography. Neither vigabatrin nor gabapentin treatment, with or without deferoxamine, led to any increase in porphyrin accumulation. Similar doses of felbamate (with deferoxamine) led to a marked increase in (mainly proto-) porphyrin levels, qualitatively and quantitatively almost identical to the accumulation produced by phenobarbital. Lamotrigine or tiagabine (with deferoxamine) caused similar porphyrin accumulation. Tiagabine treatment up to 100 microM (with deferoxamine) also resulted in very high levels of predominantly proto-porphyrin. In contrast to the other anticonvulsants tested, tiagabine without deferoxamine led to mild porphyrin accumulation. In the presence of deferoxamine, phenobarbital, felbamate, lamotrigine, or tiagabine, but not gabapentin or vigabatrin, increased levels of the mRNA of ALA synthase, the first and rate-controlling enzyme of porphyrin synthesis. Such enzyme induction is a sine qua non for acute porphyric attacks. We conclude that neither vigabatrin nor gabapentin is porphyrogenic, whereas felbamate, lamotrigine, and, especially, tiagabine lead to much accumulation of porphyrins. The latter three anticonvulsants, therefore, may precipitate or exacerbate acute porphyric attacks in humans. We recommend use of vigabatrin or gabapentin, but not felbamate, lamotrigine, or tiagabine, in patients with acute porphyria and seizures.
Animals↗
Weight variations in the prophylactic therapy of primary headaches: 6-month follow-up.
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.
Adrenergic beta-Antagonists↗
Measuring the effects of antiepileptic medications on balance in older people.
BACKGROUND: Dizziness and ataxia are among the most common adverse events associated with antiepileptic medications. Despite this, few studies have attempted to quantitatively assess the effects of antiepileptic therapies on equilibrium. This study was undertaken to prospectively compare quantitative measures of balance in older people taking carbamazepine, gabapentin and lamotrigine. METHODS: Thirty patients on monotherapy for idiopathic partial or generalized epilepsy were enrolled after giving informed consent. Patients had to be at least 50 years old, able to give consent, and on a stable dose of carbamazepine, gabapentin or lamotrigine for at least 30 days. Since this was a study of asymptomatic patients, all patients had to be without complaint of dizziness or imbalance. Patients with a history of alcohol or drug abuse or any medical or neurological condition expected to adversely affect equilibrium were excluded. Each patient underwent a history and examination, computerized dynamic posturography, the activities-specific balance confidence (ABC) scale, Fregly ataxia battery, and the Berg balance scale. Serum drug levels of carbamazepine were obtained to eliminate patients with toxic levels upon enrollment. Two-tailed paired t-tests were used to determined statistical significance among those on each antiepileptic medication. RESULTS: Thirty patients were enrolled: 10 on gabapentin, 10 on lamotrigine and 10 on carbamazepine monotherapy for epilepsy. There were no differences in age or sex among those in each treatment group. The average dosages were 1,120 mg/day for those on gabapentin, 335 mg for lamotrigine, and 640 mg for carbamazepine. There were no differences in the activities-specific balance confidence (ABC) or the Berg balance scale scores. All patients had normal vestibular function by quantitative testing. Posturography showed no statistically significant differences. The Fregly ataxia battery includes the sum of timed trials in the sharpened Romberg (SR) position, standing on one leg with eyes closed (SOLEC), and when walking in tandem with eyes closed (WITEC). The patients on lamotrigine exhibited ability to maintain balance in these positions significantly longer than did those on carbamazepine: SR (P<0.05), SOLEC (P<0.05) and WITEC (P<0.05). CONCLUSIONS: The effects of antiepileptic medications on equilibrium in asymptomatic older people may require more dynamic and challenging measures of equilibrium than are commonly employed in physical therapy to monitor risk of falls. Although the sample size is small, this study suggests that lamotrigine may induce less disequilibrium than does carbamazepine in older people on monotherapy for epilepsy. Further study in this area is needed, particularly given the risks of falling from imbalance in the elderly.
Aged↗
Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and secondary hyperalgesia.
OBJECTIVE: In the present study, we sought to develop/characterize the pain profile of a rat model of surgically induced osteoarthritis (OA). METHODS: OA was surgically induced in male Lewis rats (200-225 g) by transection of the medial collateral ligament and medial meniscus of the femoro-tibial joint. In order to characterize the pain profile, animals were assessed for a change in hind paw weight distribution (HPWD), development of mechanical allodynia, and the presence of thermal and mechanical hyperalgesia. Rofecoxib and gabapentin were examined for their ability to decrease change in weight distribution and tactile allodynia. RESULTS: Transection of the medial collateral ligament and medial meniscus of male Lewis rats resulted in rapid (<3 days) changes in hind paw weight bearing and the development of tactile allodynia (secondary hyperalgesia). There was, however, no appreciable effect on thermal hyperalgesia or mechanical hyperalgesia. Treatment with a single dose of rofecoxib (10 mg/kg, PO, day 21 post surgery) or gabapentin (100mg/kg, PO, day 21 post surgery) significantly attenuated the change in HPWD, however, only gabapentin significantly decreased tactile allodynia. CONCLUSION: The rat medial meniscal tear (MMT) model mimics both nociceptive and neuropathic OA pain and is responsive to both a selective cylooxygenase-2 (COX-2) inhibitor commonly utilized for OA pain (rofecoxib) and a widely prescribed drug for neuropathic pain (gabapentin). The rat MMT model may therefore represent a predictive tool for the development of pharmacologic interventions for the treatment of the symptoms associated with OA.
Amines↗
CHF3381, a N-methyl-D-aspartate receptor antagonist and monoamine oxidase-A inhibitor, attenuates secondary hyperalgesia in a human pain model.
UNLABELLED: CHF3381 is a new low-affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor. The analgesic activity of CHF3381 was investigated in the heat-capsaicin human pain model and compared with those of gabapentin. Twenty-seven young, healthy male volunteers received a single oral dose of CHF3381 (500 mg), gabapentin (1,200 mg), or placebo in a randomized, double-blind, crossover study design. Measurements were done before and 135 to 145 minutes after treatment administration and included area of secondary hyperalgesia around the sensitized skin of the forearm (45 degrees C for 5 minutes followed by topical capsaicin for 30 minutes), area of secondary hyperalgesia after thermal sensitization of the thigh (45 degrees C for 3 minutes), heat pain detection thresholds (degrees C), and pain on a visual analogue scale after long thermal stimulation (45 degrees C for 1 minute). Compared with placebo, both gabapentin and CHF3381 significantly reduced the area of secondary hyperalgesia on the dominant forearm. Median (and interquartile range) percent values over baseline were 86% after placebo (69% to 100%), 56% (41% to 76%) after gabapentin (P < .001), and 67% (49% to 88%) after CHF3381 (P < .009). Both drugs also significantly decreased the area of secondary hyperalgesia on the dominant thigh. The other pain variables were not significantly affected. Adverse events, mainly fatigue and dizziness, were mild to moderate. PERSPECTIVE: This article presents the antihyperalgesic effect of CHF3381, a new NMDA receptor antagonist and reversible MAO-A inhibitor, in a human pain model and might guide the proper selection of CHF3381 doses to be used in Phase 2 studies in patients with neuropathic pain.
Adult↗