Gabapentin prophylaxis for postoperative nausea and vomiting in abdominal surgeries: a quantitative analysis of evidence from randomized controlled clinical trials.

INTRODUCTION: Postoperative nausea and vomiting (PONV) is frequently encountered in the surgical recovery room. Abdominal surgery is one important risk factor for increased incidence of PONV. Gabapentin, an anticonvulsant with known postoperative analgesic properties, has shown some activity against PONV. Results from clinical trials evaluating the anti-emetic efficacy of gabapentin are conflicting. The present meta-analysis was performed to examine this issue. METHODS: Seventeen randomized placebo-controlled trials reporting PONV with preoperative gabapentin administration in patients undergoing abdominal surgery were included for analysis. Outcomes evaluated were nausea, vomiting, composite PONV and the use of rescue anti-emetic medication in the postoperative period. RESULTS: The pooled relative risk (RR), estimated using the random effects model of the metafor package for R, was 0.76 (95% CI 0.58-0.98) for nausea, 0.62 (0.45-0.85) for vomiting, 0.71 (0.39-1.28) for data represented as composite PONV (possibly biased by a single study, as observed in the sensitivity analysis), and 0.6 (0.41-0.89) for rescue anti-emetic use. There was a significant RR reduction for nausea and vomiting when propofol was not used as induction and/or maintenance for anaesthesia. In the abdominal hysterectomy subgroup, there was a significant RR reduction for vomiting but not for nausea. DISCUSSION: The present analysis provides evidence supporting preoperative gabapentin as a pharmacotherapy for prevention of PONV in patients undergoing abdominal surgeries. Future studies comparing preoperative gabapentin with 5HT3 antagonists are needed to precisely define its role in PONV.

Amitriptyline vs. pregabalin in painful diabetic neuropathy: a randomized double blind clinical trial.

AIMS: To compare the efficacy and safety of pregabalin and amitriptyline in alleviating pain associated with diabetic peripheral neuropathy. METHODS: A randomized, double-blind, crossover, active-control, clinical trial with variable dose titration was carried out (n = 51). Amitriptyline orally, at doses of 10, 25 and 50 mg at night-time and pregabalin orally, at doses of 75, 150 and 300 mg twice daily, by optional titration was used. Each drug treatment was of 5 weeks. There was a placebo washout period for 3 weeks between the two drugs. Assessment for pain relief, overall improvement and adverse events were carried out. RESULTS: Good, moderate and mild pain relief were noted in 21 (48%), 6 (13%) and 7 (15%) patients on pregabalin and 15 (34%), 5 (11%) and 12 (27%) patients on amitriptyline, respectively, by patient's global assessment of efficacy and safety. Patient and physician's global assessment, McGill pain questionnaire, Likert pain scale and Patient Global Impression of Change showed no significant difference between the treatments, although improvement with both treatments was seen from the first week. Of the 52 adverse events reported, 34 (65.4%) were with amitriptyline, drowsiness being the commonest [in 19 (43%) patients]. Pregabalin caused adverse events in 18 (25%), of which drowsiness was the most common in nine (20%) patients. The preferred pregabalin dose was 150 mg twice daily. CONCLUSIONS: As there are few differences between the two treatments in efficacy, pregabalin 150 mg twice daily might be the alternative choice as it is associated with fewer adverse effects in our population.

Evaluation of ketamine, nimodipine, gabapentin and imipramine in partial sciatic nerve transection model of neuropathic pain in rat: an experimental study.

The aim of this research is to study the effects of nimodipine, gabapentin, ketamine and imipramine in the partial sciatic nerve transection (PST) model of neuropathic pain in rats. PST was produced in young Wistar rats of either sex by partial destruction of the sciatic nerve. A decrease in the latency to paw withdrawal reaction on the hot plate was considered as development of neuropathy. The drugs were given daily from the third day of the procedure, and evaluation was done on days 7, 14, 21 and 28. There was a significant decrease (p < 0.05) in the paw withdrawal response in the nimodipine group from day 14 onward when compared with the control group. In the ketamine and imipramine group, this response was seen from day 21 onward. The effect persisted till the end of the study. There was no improvement in the gabapentin group. The results of our study show that nimodipine (dihydropyridine calcium channel blocker), ketamine (NMDA antagonist) and imipramine (tricyclic antidepressant) modulated hyperalgesia and allodynia in the PST model of neuropathy. Gabapentin (an alpha-2 delta calcium subunit blocker) did not show any effect in this model of neuropathy. The widespread use of gabapentin in various types of neuropathic pain thus needs to be reevaluated.

Evaluation of the modulatory role of nimodipine in seizures induced by kainic acid and pentylenetetrazole in mice.

The present study aimed at establishing the CD50 and CD99 doses along with complete dose-response profile of two convulsants, namely, kainic acid and pentylenetetrazole (PTZ), in mice and evaluating the modulatory role of the cerebroselective dihydropyridine calcium channel blocker nimodipine. Kainic acid and PTZ were administered intraperitoneally in a dose range of 1-30 mg kg(-1) and 35-75 mg kg(-1), respectively. Nimodipine was administered in graded doses (1-8 mg kg(-1), i.p.) with 15 min pretreatment time against CD99 doses of both kainic acid and PTZ. The effect of nimodipine in treated groups was compared with that of vehicle in control group. The CD50 and CD99 doses for kainic acid was found to be 2.5 and 7.5 mg kg(-1), while those of PTZ were found to be 50 and 75 mg kg(-1), respectively. Pretreatment with nimodipine inhibited seizures in a dose-dependent manner, in terms of both percentage of positive responders and seizure scores against CD99 doses of both kainic acid and PTZ. The results established the protective efficacy of nimodipine against both kainic acid and PTZ-induced seizures, suggesting the role of calcium ion as a common mediator for both the types of seizures. However, further studies are necessary to ascertain the exact molecular mechanism of nimodipine.

Anti-seizure efficacy of nimodipine in pentylenetetrazole and kainic acid combined seizure models in mice.

The present study aimed at establishing two models of experimental seizures by combination treatment with subconvulsive doses of PTZ and kainic acid in adult male mice and evaluating the modulatory role of cerebroselective dihydropyridine calcium channel blocker, nimodipine. The CD50 +/- SEM value for PTZ was found to be 20.00 +/- 0.92 mg/kg, ip in kainic acid (administered at per se subconvulsive dose of 1.00 mg/kg, ip) pretreated mice while CD50 +/- SEM value for kainic acid was found to be 0.30 +/- 0.08 mg/kg, ip in PTZ (administered at per se subconvulsive dose of 30.00 mg/kg, ip) pretreated mice. Nimodipine (5.00 mg/kg, ip) significantly protected the mice from seizure in both of the combination in vivo seizure models. The results suggested synergistic interaction between PTZ and kainic acid at subconvulsive dose combination while the protective efficacy of nimodipine suggested the role of calcium ion as an important mediator for the genesis of seizures.

Potentiation of antihyperalgesic activity of diclofenac by nimodipine in a formalin model of facial pain in rats.

The present study evaluates the possible role of dihydropyridine calcium channel antagonist nimodipine on diclofenac analgesia in formalin-induced facial pain model in rats. Adult Wistar rats of either sex received an injection of 50 microl of 5% v/v subcutaneous formalin into one vibrissal pad and consequent facial grooming behaviour was monitored. Animals exhibited two distinct periods of nocifensive grooming: i) an acute phase lasting 0-6 min; and ii) a tonic phase lasting 6-45 min. The individual analgesic response of nimodipine and diclofenac was noted at doses of 5, 10 and 20 mg/kg i.p. and 1, 2 and 4 mg/kg i.p., respectively, administered 5 min prior to formalin injection. Diclofenac 1, 2 and 4 mg/kg i.p. produced dose-dependent inhibition of facial grooming in both acute and tonic phases. Nimodipine per se had antihyperalgesic effect, but to a very small extent. Nimodipine 10 and 20 mg/kg significantly potentiated the subanalgesic dose of diclofenac, i.e., 0.2 mg/kg. Results of the study showed that low dose nimodipine per se has insignificant antihyperalgesic effect. However, it potentiated the subanalgesic dose of diclofenac showing a synergistic response. These results imply that nimodipine can be used as an adjunct to the treatment of various neuropathic pains, postherpetic and diabetic neuropathies but the clinical efficacy needs to be evaluated in patients.

Possible mechanisms of insulin antinociception.

The antinociceptive mechanisms of insulin are not clearly understood. It has been postulated that insulin may act as a neuromodulator. The present study investigates the possible mechanisms of insulin antinociception in mice using the tail flick test. Healthy Swiss male albino mice were treated with insulin and the antinociceptive effect of modulators of 5-HT, NMDA, dopamine, opioids, potassium and calcium channels was tested, followed by blood sugar estimation. All drug doses were given as milligrams per kilogram of body weight 30 min prior to insulin administration, except for para-chlorophenylanine (pCPA), which was given for three consecutive days per orally. Pretreatment with morphine (opioid agonist), 5-Hydroxytryptophan (5-HTP; 5-HT precursor), nicorandil (K(+) channel opener) and nimodipine (Ca(+) channel antagonist) significantly (p < 0.001) potentiated insulin antinociception, whereas naloxone (opioid antagonist), ketanserin (5-HT(2) receptor antagonist), pCPA (5-HT depleter), ondansetron (5-HT(3) receptor antagonist), L-dopa (dopamine precursor), reserpine (dopamine depleter), ketamine (NMDA receptor antagonist) and glibenclamide (K(+) channel blocker) significantly antagonized insulin antinociception (p < 0.001). Results suggest that 5-HT, dopamine, NMDA, opioidergic receptors and potassium and calcium channels play a significant role in insulin analgesia. However, detailed studies on individual mechanisms are necessary.

Prescribing patterns and cost of antihypertensive drugs in an internal medicine clinic.

BACKGROUND: Antihypertensive agents are selected primarily for their ability to prevent morbidity and mortality related to hypertension. METHODS AND RESULTS: Prescribing trends and the cost of antihypertensive drugs were studied in 300 patients attending an internal medicine clinic. Beta-blockers were the most frequently used group of drugs (46.7%), followed by calcium-channel antagonists (34.3%) and angiotensin-converting enzyme inhibitors (30%). Diuretics were used in only 13.2% of the prescriptions. Atenolol (36%), amlodipine (29.3%) and enalapril (19%) were the most frequently used individual drugs. Propranolol, furosemide, amlodipine and atenolol were the least expensive drugs used, with annual drug acquisition costs of Rs 80, 102, 182 and 318, respectively. Benazepril (Rs 1778), diltiazem SR (Rs 1777), lisinopril (Rs 1660), prazosin (Rs 1416) and losartan (Rs 1365) were the most expensive drugs in terms of annual drug acquisition costs. CONCLUSIONS: The results of our study emphasize the need to encourage frequent use of diuretics. Since the costs of different antihypertensives vary considerably, newer and relatively expensive antihypertensives should be prescribed only when clearly indicated.

Patient compliance: the cornerstone of successful therapeutics.

In this review, it has been emphasized that the health professional plays a very important role in ensuring patient compliance. Though a variety of methods and tools have been discussed to improve patient compliance, the content and quality of communication between the patient and the physician is crucial in preventing, identifying and resolving non-compliance problems.

Investigation of central mechanism of insulin induced hypoglycemic convulsions in mice.

Insulin produces seizures in healthy and diabetic animals. Amongst suggested mechanisms, the role of neuromodulators and neurotransmitters is not clear. The present study explores the mechanisms involved in insulin-induced convulsions. Convulsions were induced in Swiss male albino mice with graded doses of insulin. Blood sugar levels were measured prior to and after the first convulsion. Drugs like 5-HTP (5-HT precursor), pCPA (5-HT depletor), ondansetron (5-HT3 antagonist), ketanserin (5-HT, antagonist), ketamine (NMDA antagonist), 1-dopa (dopamine precursor) and reserpine (amine depletor) were studied for interaction with convulsive behaviour induced by insulin. Insulin in 2 IU/kg dose did not produce convulsions while 4 and 8 IU/kg doses produced convulsions in 50% and 100% of animals respectively. 5-HTP, ondansetron, ketanserin, ketamine and l-dopa significantly protected/inhibited animals from convulsions at all studied doses of insulin. On the contrary, pCPA and reserpine potentiated insulin induced convulsions. Insulin caused mortality in 40 and 100% animals with 4 and 8 IU/kg doses respectively. pCPA and reserpine treatments caused mortality at all doses of insulin, while other drugs did not influence insulin induced mortality. Blood sugar levels were reduced in all groups irrespective of the presence or absence of convulsions. A definitive link of serotonergic, dopaminergic and excitatory amino acid pathways in mediating insulin-induced hypoglycemic convulsions is suggested.

Studies on peripheral actions of isatin.

The possible peripheral actions of isatin were studied in vivo and in vitro preparations in different experimental models, using conventional techniques. The results showed spasmogenic responses of isatin on guinea pig, rat and rabbit ileum and fundus of rat stomach. Histamine induced broncho-constriction could be antagonised by isatin. Isatin had cardioinhibitory effect on isolated frog heart and had hypotensive and respiratory depressant activities in dog. Isatin had antidiuretic effect. It was devoid of any effect on inflammation and gastric activities. The present results suggest a possible involvement of heterogenic 5-HT3 receptors in gastrointestinal smooth muscle.

Role of prostaglandin synthesis inhibitors on chemically induced seizures.

The study was conducted to find out the possible role of prostaglandin synthesis inhibitors on different parameters of chemically induced seizures in albino mice. The results suggest that prostaglandins have a proconvulsant activity. Augmentation of central dopamine and serotonin levels is partly responsible for the inhibitory effect of prostaglandin synthesis inhibitors on chemically induced seizures.

Biologics in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic progressive disease of the joints associated with significant morbidity, deformity, and impaired quality of life. A satisfactory remission of disease is seldom achieved, so therapy is aimed at controlling joint damage and pain with preservation of joint mobility. Until recently, NSAIDs, followed by DMARDs, was considered the treatment of choice. However, many patients fail to gain a satisfactory response to DMARDs or response declines over time. Biologics such as IL-1 receptor antagonist (anakinra), and anti TNF-alpha agents (Etanercept, Infliximab, and Adalimumab) are now available. The anti TNF and IL-1 therapies exert their anti-inflammatory action by neutralizing the activities of TNF-alpha and IL-1 respectively. In contrast to older DMARDs, these agents have rapid onset of action with fewer side effects and have pronounced disease reducing activity in patients who have previously been treated with other DMARDs, when administered as monotherapy or in combination with methotrexate. They have been shown to be at least as effective as methotrexate in reducing clinical disease activity and reducing radiographic progression. Biological agents are generally well tolerated, although their long-term safety needs to be determined. Some concerns have been raised that anti TNF-alpha therapy can increase the risk of serious infections, since TNF-alpha plays an important role in host defense. In light of limitations of cost and lack of long-term safety and efficacy data, newer agents for the time being are used as second- or third-line agents in patients with active RA. The dilemma is that which patients with RA are most suitable for such therapy, since it is still not possible to accurately predict which patient with RA will develop severe disease. One alternative approach may be to limit the use in patients who can afford it, and who are at high risk of radiographic progression and disability.

Neuropharmacological studies on Fusarium toxins-III: Neurochemical investigations on total toxin extracts from F. moniliforme and F. oxysporum.

Neurochemical effects of different fusarial toxins elaborated from F. moniliforme (FM) and F. oxysporum (FO) were investigated. FM showed significant nonspecific and irreversible monoamine oxidase (MAO) inhibition which was qualitatively comparable to that induced by nialamide, a nonselective MAO inhibitor. FO did not exhibit any significant MAO inhibitory effect. FM produced a dose related increase in monoamine concentrations (dopamine, noradrenaline and 5-hydroxytryptamine) in different rat brain areas namely, diencephalon-midbrain, caudate nucleus and pons-medulla. FO, on the contrary, produced marked increase in dopamine concentration in the caudate nucleus with concomitant reduction in noradrenaline levels in diencephalon-midbrain and pons-medulla with little effect on 5-HT concentration. The neurochemical effects of FM and FO are consonant with the earlier reports on the neuropharmacological profile of these toxins. Thus, FM was reported to have nialamide like activity, whereas FO actions were dopaminergic in nature.

Neuropharmacological studies on Fusarium toxins--I: Total toxin extract from Fusarium moniliforme.

The neuropharmacological profile of the total fungal extract of F. moniliforme (FM) has been investigated. FM produced dose related decrease in spontaneous motor activity (SMA) and exploratory activity, potentiated pentobarbitone hypnosis and the anticonvulsant actions of phenobarbitone and phenytoin against MES seizures, potentiated PTZ and tryptamine seizures, antagonised reserpine induced syndrome, attenuated tetrabenazine and morphine induced catalepsy and potentiated haloperidol catalepsy. FM showed per se antinociceptive activity and potentiated morphine analgesia. It increased rectal temperature, antagonised reserpine and apomorphine hypothermia and potentiated the hyperthermic response of haloperidol and 5-hydroxytryptophan (5-HTP) and hypothermic response of betaphenylethylamine (PEA) and L-dopa. FM had no per se effect on amphetamine lethality, but enhanced the lethality induced by morphine in aggregated animals. Stereotypy by amphetamine was potentiated while that of apomorphine was not affected. The behavioural response of 5-HTP and L-dopa was potentiated. FM had no effect on swim induced behavioural despair. The effect on aggressive behavior was complex, and while the cumulative aggressive score was reduced, the onset of fighting behaviour and contact period was increased. It also inhibited clonidine induced auto mutilation. Since earlier investigation had shown that FM, like nialamide, induced non-selective inhibition of monoamine oxidase (MAO), the results were compared with those induced by nialamide. A comparative profile of action reveals that the neuropharmacological action of FM are qualitatively similar to those induced by nialamide, and likely to be due to inhibition of MAO. The investigation has practical implications because F. moniliforme is a common contaminant of cereals and fruits.

Neuropharmacological studies on Fusarium toxins--II: Total toxin extract from F. oxysporum.

The neuropharmacological activity profile of total fungal extract of F. oxysporum (FO) was investigated. FO enhanced spontaneous locomotor activity, exploratory behaviour and reduced pentobarbitone hypnosis. It had per se anticonvulsant action against maximal electroshock seizure (MES) and potentiated phenobarbitone and phenytoin in MES and also potentiated pentylenetetrazol (PTZ) convulsion. It antagonised morphine, tetrabenazine and haloperidol catalepsy. FO did not show per se analgesia or potentiation of morphine antinociception in mice, while both effects were present in rats. The effect of FO on body temperature was complex. It produced per se reduction in rectal temperature and potentiated the hypothermic responses of reserpine, apomorphine, PEA and I-dopa, and also the hyperthermic response of 5-HTP. The hyperthermic response of haloperidol was reversed by FO. It potentiated amphetamine and morphine lethality, amphetamine, PEA and apomorphine stereotypy, 5-HTP headtwitch response and post-swim grooming response. On swim-stress immobility, while the time of onset of immobility was reduced, FO did not modify the duration of immobility. On foot-shock induced aggression in paired rats, FO produced a decrease in the latency to onset of fighting behaviour and increased the total contact period and the cumulative aggressive score. FO potentiated clonidine automutilation. It has, thus, facilitated aggressive behaviour. The effects are likely to be due to the presence of fusaric acid in FO, which inhibits dopamine beta-hydroxylase and is known to have dopaminergic effects. This investigation has practical implications. since F. oxysporum is a common food contaminant.

Randomized double-blind study comparing the efficacy and safety of lamotrigine and amitriptyline in painful diabetic neuropathy.

AIMS: To compare the efficacy and safety of lamotrigine and amitriptyline in controlling chronic painful peripheral neuropathy in diabetic patients. METHODS: A randomized, double-blind, crossover, active-control, clinical trial with variable dose titration was carried out (n = 53). Amitriptyline orally, at doses of 10, 25 and 50 mg at night-time, each dose for 2 weeks, and lamotrigine orally, at doses of 25, 50 and 100 mg twice daily, each dose for 2 weeks, by optional titration were used. There was a placebo washout period for 2 weeks between the two drugs. Assessment for pain relief, overall improvement and adverse events were carried out. RESULTS: Good, moderate and mild pain relief were noted in 19 (41%), six (13%) and seven (15%) patients on lamotrigine and 13 (28%), five (11%) and 15 (33%) patients on amitriptyline, respectively, by patient's global assessment of efficacy and safety. Patient and physicians global assessment, McGill pain questionnaire and Likert pain scale showed no significant difference between the treatments, although improvement with both treatments was seen from 2 weeks. Of the 44 adverse events reported, 33 (75%) were with amitriptyline, sedation being the commonest [in 19 (43%) patients]. Lamotrigine caused adverse events in 11 (25%), of which rash in three (7%) and elevations of creatinine in four (9%) were the most common. The preferred lamotrigine dose was 25 mg twice daily. CONCLUSIONS: As there are few differences between the two treatments in efficacy, lamotrigine 25 mg twice daily might be the first choice as it is associated with fewer adverse effects in our population.

Study of association between use of complementary and alternative medicine and non-compliance with modern medicine in patients presenting to the emergency department.

CONTEXT: Complementary and alternative medicines (CAMs) are extensively used by the public. Noncompliance is an important cause of therapy failure. AIM: This study was done to determine prevalence of emergency admission due to noncompliance with modern medicine following switching over to CAM and to identify any significant association for CAM use among noncompliers. SETTING AND DESIGN: This cross-sectional study was conducted in the emergency unit of a tertiary healthcare institute. MATERIALS AND METHODS: Demographic factors and system affected were compared between compliers and noncompliers. Prevalence, reasons and nature of noncompliance were determined. Age, gender, outcome, relation strength and potential preventability of noncompliance, precipitating and previous disease and noncompliant drugs were compared for significant association between CAM using and other noncompliers. STATISTICAL ANALYSIS: Student's 't' test, Chi square test and odds ratio were used. RESULTS: Of the 506 patients interviewed 168 (33%) were noncompliant. In 160 (95%) patients noncompliance was due to under-dosing. Lack of knowledge and CAM use constituted 144 (86%) noncompliance-related admissions. Thirty-three (7%) admissions were strongly related to noncompliance and CAM use. Age, gender, outcome, drug use and diseases except chronic obstructive pulmonary disease (COPD) and asthma showed no association while relation strength and potential preventability of emergency admission was less with CAM-using noncompliers. Noncompliance was observed for hypertension, diabetes, COPD and asthma, seizure disorder, tuberculosis and hemophilia besides hepatic and renal failure. The CAM noncompliers used CAM more for modern medicine incurable or unaffordable than curable diseases. CONCLUSION: Advice for regular treatment and frequent monitoring can decrease CAM use-related noncompliance admissions.

Advanced prostatic carcinoma in a 19-year-old male.

We report a case of poorly differentiated carcinoma of the prostate with lymph node metastasis in a 19-year-old male. He was managed with bilateral orchiectomy, flutamide and recombinant interferon alfa-2b therapy. He showed subjective improvement for 2 months. However, during the 3rd month of treatment there was global deterioration which progressed further till his demise during the 4th month. The beneficial role, if any, of combined hormonal and immunotherapy in advanced prostatic carcinoma is discussed as also the natural history and prognosis of prostatic carcinoma in men under 20 years of age.

Fibrocalculus pancreatic diabetes in western Orissa.

Skiagram proved 35 cases of fibrocalculus pancreatic diabetes in order to analyse the clinical profile and its correlation with different descriptive epidemiological parameters were studied. Mean age was 25.17 +/- 7.85 years and male to female ratio was 6:1; 65.7% patients were poor (income < Rs 500 per month) and another 28.6% having average income (Rs 500 to Rs 1,000 per month); 74.3% came from rural areas having a family size of about > or = 7 members and sanitation was poor in all the cases. Mean body mass index was 15.93 +/- 3. Severe diabetes (ie, fasting blood sugar level > 251 mg%) and moderately severe diabetes (ie, fasting blood sugar level > 181 mg% but < 250 mg%) were noted in 51.4% and 11.4% cases respectively. Recurrent pain abdomen, infections, neuropathy, retinopathy, nephropathy and keto-acidosis were observed in 52.2%, 40.0%, 42.9%, 8.6%, 11.4% and 2.9% cases respectively. Mean soluble insulin requirement was 41.81 +/- 13.94 units. Four cases in whom pancreatic lithotomy was done, showed less insulin requirement and disappearance of pain. Parotid swelling, chronic diarrhoea and insulin resistance were not observed. Insulin requirement, epidemiological and biochemical parameters were similar to other young diabetics.