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Orofacial neuralgia. Diagnosis and treatment guidelines.

Patients with facial pain, without overt dental disease, are often seen in both medical and dental practice. The differential diagnosis includes (a) cluster headache, in which patients have severe unilateral pains lasting 30 to 120 minutes that respond to verapamil, corticosteroids or lithium; (b) migraine, in which attacks are longer and are often accompanied by nausea and visual disturbance, and can be managed using anti-inflammatory analgesics, with or without metoclopramide, or sumatriptan, although frequent attacks are best suppressed by continuous propranolol or pizotifen; (c) trigeminal neuralgia, knifelike unilateral pains usually responsive to carbamazepine; and (d) temporal arteritis, a steadier pain very responsive to corticosteroids. There is no evidence that continuous 'idiopathic facial pain' is a result of malocclusion (i.e. the way in which the teeth fit together), and its aetiology remains obscure, although there is some biochemical evidence linking it to depression. Many patients respond to simple analgesia and firm reassurance from the physician, although antidepressant therapy (e.g. nortriptyline or dothiepin) is often of great value.

Anti-Inflammatory Agents↗

Advances in non-nicotine pharmacotherapy for smoking cessation.

Progress in understanding the pharmacological nature of tobacco addiction, along with the modest success rates achieved by the nicotine replacement therapies, has provided the major impetus for the development of non-nicotine drugs as smoking cessation aids. This article reviews evidence from controlled trials of several non-nicotine medications for the treatment of nicotine dependence. Clonidine was the first non-nicotine medication to show efficacy for smoking cessation in multiple studies, but its effect was found to be limited at best. Positive results across several trials have been consistently demonstrated for amfebutamone (bupropion). Encouraging results have also been observed for nortriptyline and moclobemide. Studies of combined treatments using non-nicotine medications (amfebutamone, mecamylamine, oral dextrose) with nicotine replacement therapy suggest increased efficacy relative to treatments using one or the other treatment strategy alone. Thus, available evidence indicates that non-nicotine drug treatments offer a promising panoply of therapeutic strategies for the addicted smoker.

Antidepressive Agents↗

Pharmacoeconomic analysis of venlafaxine in the treatment of major depressive disorder.

We conducted a cost-effectiveness analysis of acute major depressive disorder (MDD) using serotonin-norepinephrine reuptake inhibitors (SNRIs; venlafaxine), selective serotonin reuptake inhibitors (SSRIs; fluoxetine, fluvoxamine, sertraline, paroxetine), or tricyclic antidepressants (TCAs; amitriptyline, imipramine, desipramine, nortriptyline). A decision-tree model over 6 months was constructed using an expert panel. The analytic perspective was that of the Ontario Ministry of Health as payor for all direct costs, which were derived from standard lists and included the cost of the drug as well as those for medical care, laboratory services, hospitalisation and managing adverse events. Success and dropout rates were determined from a meta-analysis of published randomised controlled trials. Medline, Embase, and International Pharmaceutical Abstracts were searched from 1984 to 1996, as were references from retrieved articles and reviews. Inpatients and outpatients were analysed separately. SSRIs were used as backup therapy for patients receiving venlafaxine and TCAs, and SNRIs were used as backup therapy for patients receiving SSRIs. Pharmacoeconomic outcomes were expected cost per success, expected cost per symptom free day (SFD), and incremental cost per success and per SFD. The meta-analysis identified 56 treatment arms from 36 randomised controlled trials involving 2953 patients (2380 outpatients and 573 inpatients). SNRIs had the highest success rates. The respective costs (in 1996 $Can; $Can1 = $US0.74) for outpatients and inpatients are given below. The expected costs per success were $6044 and $17,234 for venlafaxine, $6634 and $20,874 for SSRIs, and $9035 and $20,459 for TCAs in outpatients and inpatients, respectively. The respective expected costs per SFD were $45.92 and $127.31 for venlafaxine, $51.64 and $157.04 for SSRIs, and $70.71 and $152.43 for TCAs. Venlafaxine was dominant for all incremental pharmacoeconomic analyses. Sensitivity analyses indicated that the results were robust for outpatients but somewhat sensitive for inpatients. In conclusion, venlafaxine is a cost-effective drug for the treatment of MDD in adult outpatients and inpatients.

Antidepressive Agents, Second-Generation↗

Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective.

Many psychiatric patients smoke, and are believed to be heavier smokers than those without psychiatric disorders. Cigarette smoking is one of the environmental factors that contributes to interindividual variations in response to an administered drug. Polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke induce hepatic aryl hydrocarbon hydroxylases, thereby increasing metabolic clearance of drugs that are substrates for these enzymes. PAHs have been shown to induce 3 hepatic cytochrome P450 (CYP) isozymes, primarily CYP1A1, 1A2 and 2E1. Drug therapy can also be affected pharmacodynamically by nicotine. The most common effect of smoking on drug disposition in humans is an increase in biotransformation rate, consistent with induction of drug-metabolising enzymes. Induction of hepatic enzymes has been shown to increase the metabolism and to decrease the plasma concentrations of imipramine, clomipramine, fluvoxamine and trazodone. The effect of smoking on the plasma concentrations of amitriptyline and nortriptyline is variable. Amfebutamone (bupropion) does not appear to be affected by cigarette smoking. Smoking is associated with increased clearance of tiotixene, fluphenazine, haloperidol and olanzapine. Plasma concentrations of chlorpromazine and clozapine are reduced by cigarette smoking. Clinically, reduced drowsiness in smokers receiving chlorpromazine, and benzodiazepines, compared with nonsmokers has been reported. Increased clearance of the benzodiazepines alprazolam, lorazepam, oxazepam, diazepam and demethyl-diazepam is found in cigarette smokers, whereas chlordiazepoxide does not appear to be affected by smoking. Carbamazepine appears to be minimally affected by cigarette smoke, perhaps because hepatic enzymes are already stimulated by its own autoinductive properties. Cigarette smoking can affect the pharmacokinetic and pharmacodynamic properties of many psychotropic drugs. Clinicians should consider smoking as an important factor in the disposition of these drugs.

Animals↗

The management of tricyclic antidepressant poisoning : the role of gut decontamination, extracorporeal procedures and fab antibody fragments.

Although there have been descriptive, uncontrolled clinical reports of removal of tablet debris by gastric lavage, there have been no clinical studies that have demonstrated that this has any impact on outcome in patients with tricyclic antidepressant (TCA) poisoning. There is also the possibility that lavage may increase drug absorption by pushing tablets into the small intestine. Furthermore, gastric lavage in patients with TCA poisoning may induce hypoxia and a tachycardia potentially increasing the risk of severe complications such as arrhythmias and convulsions. In view of the paucity of evidence that gastric lavage removes a significant amount of drug and the risk of complications associated with the procedure, the routine use of gastric lavage in the management of patients with TCA poisoning is not appropriate. Volunteer studies have shown generally that activated charcoal is more likely to reduce drug absorption if it is administered within 1 hour of drug ingestion. In the one volunteer study that looked at later administration of activated charcoal, there was a 37% decrease in plasma concentration associated with administration of activated charcoal at 2 hours post-ingestion. There have been no clinical studies that enable an estimate of the effect of activated charcoal administration on outcome in the management of patients with TCA poisoning. Volunteer studies have shown that multiple-dose activated charcoal increases the elimination of therapeutic doses of amitriptyline and nortriptyline, but not of doxepin or imipramine; however, these studies cannot be directly extrapolated to the management of patients with TCA poisoning. There have been no well designed controlled studies that have assessed the impact of multiple-dose activated charcoal in the management of patients with TCA poisoning. Because of the large volume of distribution of TCAs, it would not be expected that their elimination would be significantly increased by multiple-dose activated charcoal.Haemoperfusion, haemodialysis and the combination of these procedures do not result in significant removal of TCAs and are not recommended in the management of patients with TCA poisoning.

Animals↗

Male sexual side effects associated with antidepressants: a descriptive clinical study of 32 patients.

OBJECTIVE: This is a retrospective study to add to the existing body of clinical information regarding male sexual side effects associated with antidepressants. From the chart review, thirty-four out of eighty male patients were identified to have reported loss of libido, erectile difficulty, anorgasmia, and delayed ejaculation while receiving pharmacotherapy of selective serotonin reuptake blockers (fluoxetine, paroxetine, and sertraline); tricyclic antidepressants (nortriptyline, imipramine, amitriptyline, desipramine, and clomipramine); and a monoamine oxidase inhibitor (phenelzine). METHOD: The authors also discussed the management of these sexual side effects by waiting for spontaneous remission, reducing the dosage level, and substituting the offending drug with other antidepressants. RESULTS: This article underscores the underreported nature of antidepressant-associated sexual dysfunction, the high incidence of SSRI-associated sexual side effects, equal potentials in causing sexual side effects among the three SSRI's, the low incidence rate of sexual adverse effects from bupropion, and the minimal need to add an antidote if the side effects are to be managed systematically. CONCLUSIONS: Finally, male sexual side effects can occur randomly and involve any sexual phase randomly, and the treatment approaches are similar, regardless of the types of sexual dysfunction associated with antidepressants.

Adult↗

Some aspects of genetic polymorphism in the biotransformation of antidepressants.

Tricyclic antidepressants are all hydroxylated by cytochrome P450 (CYP) 2D6, but the tertiary amines, amitriptyline, clomipramine and imipramine, are also N-demethylated to the active metabolites, nortriptyline, N-desmethylclomipramine and desipramine, by several CYPs, including the polymorphic CYP2C19, CYP1A2 and CYP3A4. The five selective serotonin reuptake inhibitors, citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are also oxidised by the CYP enzyme system. Thus, fluoxetine, fluvoxamine and paroxetine are partially metabolised by CYP2D6, citalopram by CYP2C19 and sertraline by at least five different CYPs. Paroxetine and fluoxetine are very potent inhibitors of CYP2D6 while citalopram, fluvoxamine and sertraline are moderate inhibitors of this enzyme. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19 and a moderate inhibitor of CYP2C9. Since the termination of the human genome project, there is no longer a technical hindrance to the identification of all of the genes involved in the clinical response to antidepressants. Research in the future will involve modern technologies and new scientific disciplines, including DNA-micro-array technology and bioinformatics. The research ultimately aims at developing better and safer antidepressants and/or better and safer use of currently available antidepressants.

Animals↗

Transcranial AC pulsed applications of weak electromagnetic fields reduces freezing and falling in progressive supranuclear palsy: a case report.

Freezing is a common and disabling symptom in patients with Parkinsonism. It affects most commonly the gait in the form of start hesitation and sudden immobility often resulting in falling. A higher incidence of freezing occurs in patients with progressive supranuclear palsy (PSP) which is characterized clinically by a constellation of symptoms including supranuclear ophthalmoplegia, postural instability, axial rigidity, dysarthria, Parkinsonism, and pseudobulbar palsy. Pharmacologic therapy of PSP is currently disappointing and the disease progresses relentlessly to a fatal outcome within the first decade after onset. This report concerns a 67 year old woman with a diagnosis of PSP in whom freezing and frequent falling were the most disabling symptoms of the disease at the time of presentation. Both symptoms, which were rated 4 on the Unified Parkinson Rating Scale (UPRS) which grades Parkinsonian symptoms and signs from 0 to 4, with 0 being normal and 4 being severe symptoms, were resistant to treatment with dopaminergic drugs such as levodopa, amantadine, selegiline and pergolide mesylate as well as with the potent and highly selective noradrenergic reuptake inhibitor nortriptyline. Weekly transcranial applications of AC pulsed electromagnetic fields (EMFs) of picotesla flux density was associated with approximately 50% reduction in the frequency of freezing and about 80-90% reduction in frequency of falling after a 6 months follow-up period. At this point freezing was rated 2 while falling received a score of 1 on the UPRS. In addition, this treatment was associated with an improvement in Parkinsonian and pseudobulbar symptoms with the difference between the pre-and post EMF treatment across 13 measures being highly significant (p < .005; Sign test). These results suggest that transcranial administration AC pulsed EMFs in the picotesla flux density is efficacious in the treatment of PSP.

Accidental Falls↗

Quaternary N-glucuronides of 10-hydroxylated amitriptyline metabolites in human urine.

1. Conjugated metabolites were isolated from the urine of patients receiving amitriptyline treatment using a combination of solid-phase extraction, h.p.l.c. and t.l.c. 2. By n.m.r. and mass spectrometry, N-glucuronides of E- and Z-10-hydroxyamitriptyline and of trans-10,11-dihydroxyamitriptyline were identified in addition to the previously described O-glucuronides of E- and Z-10-hydroxyamitriptyline and -nortriptyline and amitriptyline-N-glucuronide. 3. The quaternary ammonium glucuronides proved to be resistant to acid hydrolysis, but could be cleaved enzymatically. 4. In urine samples from three patients, 35-60% of conjugated 10-hydroxyamitriptyline was found in the form of N-glucuronides. 5. A volunteer given an i.v. infusion of amitriptyline-N-glucuronide excreted E- and Z-10-hydroxyamitriptyline-N-glucuronide; following ingestion of E-10-hydroxyamitriptyline its N-glucuronide could be measured in urine.

Adult↗

Recent developments in drug metabolism of relevance to psychiatrists.

The discovery in 1977 of stable genetic differences (polymorphisms) in the oxidative metabolism of debrisoquine (P450 2D6) has led to an increasingly rapid growth in knowledge concerning the diversity of cytochrome P450 enzymes, their substrate-specific metabolism, and their interindividual variation. The current state of this knowledge for cytochromes P450 2D6, 2C19, 1A2, 3A3, and 2E1 is summarized, with a view toward their potential relevance to clinical psychopharmacology. To date, no prospective trials have tested the application of clinical tests of drug metabolism to treatment with psychotropics, and no guidelines have been formulated for such an application. The author reports preliminary findings from his studies of P450 2D6 phenotyping in elderly patients treated with nortriptyline and perphenazine. Research in this area may lead to earlier identification of patients at risk because of atypical drug metabolism. This might reduce drug-drug interactions, overmedication, or inadequate treatment.

Biotransformation↗

Cardiovascular changes and plasma drug levels after amitriptyline overdose.

Electrocardiographic and blood pressure parameters in 17 patients after amitriptyline overdose were reviewed in a retrospective study. Seven patients for whom baseline electrocardiograms (EKGs) were available showed significant increases in heart rate and QRS duration after overdose. Ventricular arrhythmias were observed in only one case, the sole fatality, who demonstrated the highest amitriptyline plus nortriptyline plasma level. Most patients experienced sinus tachycardia (88%) and hypotension (53%). Widened PR and QRS after overdose also were common. For the total group, postoverdose TCAD levels correlated with PR (r = .66, p less than .01) and QRS (r = .55, p less than .05) values, and with lowest observed systolic (r = -.60, p = .01) and diastolic blood pressure (r = .50, p less than .05) but not QTc or heart rate. The difference between the mean TCAD levels of subjects with lowest systolic blood pressure less than 100 mmHg and those with higher readings was significant at the 0.05 level.

Adolescent↗

Tobacco cessation in primary care: maximizing intervention strategies.

The most effective preventive intervention that a clinician can provide for tobacco-using patients against heart disease, cancer, cerebrovascular disease and chronic obstructive pulmonary disease is an empathic, personalized smoking cessation intervention program with extended assistance and follow-up. The goal of the intervention must be complete smoking cessation. Reduction provides no direct health benefits to the individual smoker. Interventions are readily available, but underutilized, in part due to lack of clinician training and organizational support. The present article summarizes the current guidelines for smoking cessation interventions as a framework from which to start. The guidelines incorporate the Transtheoretical Model of patient behavioral change and the "Five A's": Ask, Advise, Assess, Assist and Arrange. Pharmacotherapeutic tools, including nicotine replacement therapies (nicotine gums, patches, nasal sprays, inhalers and new therapies) and non-nicotine therapies (bupropion, clonidine, nortriptyline and other antidepressants and anxiolytics) are considered. Adherence validation methods, new approaches to tobacco and addiction treatment that appear in the recent research literature are reviewed. Beyond this framework, specific categories of tobacco users (including smokeless tobacco users), cultural and ethnic minorities, adolescents using snuff and bidis, women, Medicaid recipients, and users of multiple forms of tobacco require special consideration. With this framework and the modifications that may be required for specific categories of patients, practicing clinicians can incorporate into daily practice a successful tobacco cessation intervention program with quit rates approaching 20%.

Humans↗

The effectiveness of various postpartum depression treatments and the impact of antidepressant drugs on nursing infants.

BACKGROUND: Postpartum depression is seen in approximately 13% of women who have recently given birth; unfortunately, it often remains untreated. Important causes for undertreatment of this disorder are providers' and patients' lack of information about the effectiveness of various treatments, and their concerns about the impact of treatment on nursing infants. This article presents research-based evidence on the benefits of various treatments for postpartum depression and their potential risks to nursing infants. METHODS: The medical literature on postpartum depression treatment was reviewed by searching MEDLINE and Current Contents using such key terms as "postpartum depression," "treatment," "therapy," "psychotherapy," and "breastfeeding." RESULTS AND CONCLUSIONS: There is evidence that postpartum depression improves with antidepressant drug therapy, estrogen, individual psychotherapy, nurse home visits, and possibly group therapy. Of the more frequently studied antidepressant drugs in breastfeeding women, paroxetine, sertraline, and nortriptyline have not been found to have adverse effects on infants. Fluoxetine, however, should be avoided in breastfeeding women. By administering effective treatment to women with postpartum depression, we can positively impact the lives of mothers, their infants, and other family members.

Antidepressive Agents↗

Risk factors for falls during treatment of late-life depression.

BACKGROUND: Prior studies have found that antidepressant medications are associated with an increased risk of falling in elderly persons. However, little is known about the prevention of falls during treatment for depression in elderly persons. This study evaluated the time course and potential risk factors for falls in a treatment protocol for late-life depression to identify specific at-risk periods and risk factors for falls in this population. METHOD: One hundred four subjects aged 69 years and over were treated in a protocolized manner using paroxetine and interpersonal psychotherapy. Those who did not respond received augmentation therapy with bupropion, nortriptyline, or lithium. Subjects were assessed at baseline and weekly during treatment; demographic and clinical characteristics of those who experienced a fall during treatment were compared with those who did not fall. Cox proportional hazards models were used to define risk factors for falls in univariate and multivariate models. RESULTS: During a mean of 21 weeks of treatment, 40 subjects (38%) fell. About half (53%) of the subjects fell during the first 6 weeks of treatment. In the multivariate model, memory impairment and orthostatic changes in blood pressure during treatment were risk factors for falling. Additionally, augmentation with bupropion appeared to be a risk factor for falls in univariate analysis, but this result is preliminary due to the small number of subjects who took bupropion. CONCLUSION: Increased monitoring for falls is warranted during the acute treatment of late-life depression. When treating such patients, clinicians should be especially watchful of those with memory impairments or those who develop orthostatic blood pressure changes; orthostatic blood pressure should be measured throughout acute treatment. Additionally, augmenting paroxetine with bupropion may also increase the risk of falls, and this medication combination should be used with caution in elderly patients.

Accidental Falls↗

A brief review of pharmacotherapies for smoking cessation.

The U.S. Department of Health and Human Services' Clinical Practice Guidelines have established both nicotine and nonnicotine-based pharmacotherapies as efficacious treatments for smoking cessation. Smokers attempting to quit smoking can significantly increase their chances by using one of several first-line agents, including nicotine transdermal patches, gum, nasal spray, inhalers, tablets, and the antidepressant bupropion. Those who cannot use either bupropion or nicotine replacement therapy because of contraindications or lack of effectiveness may benefit from the second-line treatment nortriptyline. This article also discusses several novel compounds for smoking cessation.

Antidepressive Agents↗

[Treatment of different types of pain].

Accurate assessment of pain is the key to appropriate analgesia. This necessitates not only an understanding of the organic component, but also a comprehension of the role played by the mental, social and spiritual dimensions in the individual patient's suffering. It implies that the entire care team must be involved in pain management. The nature of a patient's pain is one predictor of the response to treatment. It is mainly characterized by its location, intensity, extent, timing and type (excessive nociception, neurogenic, or mixed), the circumstances in which it appears, and any accompanying signs. The choice of analgesic for treating pain due to excessive nociception was greatly facilitated by the introduction of the WHO three-step approach. Better knowledge of the pharmacological and pharmacokinetic properties of the different analgesics has contributed to increase their efficacy and tolerability. Certain types of pain of neurogenic origin respond poorly to both opiate and non opiate analgesics. They can be treated with other drugs whose mechanisms of action in pain relief are not fully understood. They include the following; antidepressants (amitriptyline, nortriptyline, desipramine and doxepine); anticonvulsants (carbamazepine, phenytoin, valporic acid and clonazepam); antiarrhythmic agents (lidocaine, mexiletine, flecainide and tocainide). The unwanted effects of these different treatments, together with psychological disturbances induced by the underlying disease, can call for the use of antiemetics, laxatives, spasmolytics, glucocorticoids and psychotropic agents (anxiolytics, neuroleptics and antidepressants). Finally, in many cases, better pain relief is obtained by combining drug-based therapy with other interventions such as radiation therapy, neurosurgery, and psychological/behavioral approaches. All these means must be chosen and used according to each individual patient's needs. Pain must be considered as a disease that can and must be eliminated or at least attenuated.

Analgesics, Non-Narcotic↗

Microsomal binding of amitriptyline: effect on estimation of enzyme kinetic parameters in vitro.

The effect of binding of amitriptyline to human liver microsomes and to microsomes from human B-lymphoblastoid cells on the estimation of enzyme kinetic parameters describing N-demethylation to nortriptyline was investigated using a combination of microsomal binding and in vitro enzyme kinetic studies. Quantitative binding in both matrices increased with higher microsomal protein concentrations (free fractions 0.88-0.32 at 100-500 microg protein/ml in human liver microsomes and 0.82-0.26 at 250-1000 microg protein/ml in microsomes from B-lymphoblastoid cells) and was independent of amitriptyline concentration over a concentration range of 0.2 to 200 microM. Addition of heat-inactivated microsomal protein (50-450 microg/ml) to native human liver microsomes (50 microg/ml) reduced the amitriptyline N-demethylation rate in a protein concentration dependent manner. This effect was greater at lower substrate concentrations and was overcome by saturating concentrations of substrate, thereby decreasing the apparent affinities of the high- and low-affinity components of the N-demethylation process, with minimal effect on the net V(max). Addition of metabolically inactive microsomes from untransfected human lymphoblastoid cells (750 microg/ml) to CYP2C19 (250 microg/ml protein) increased the apparent K(m) value for amitriptyline N-demethylation by 3.5-fold and increased the uncompetitive substrate inhibition constant (K(s)) by 2.2-fold, making substrate inhibition essentially undetectable. A similar effect was seen with CYP3A4, with a 1.8-fold increase in the S(50) (substrate concentration at which half-maximal velocity of a Hill enzyme is achieved). Microsomal binding did not alter the V(max) of either CYP isoform to any appreciable extent. These findings emphasize the importance of incorporating microsomal binding in the estimation of enzyme kinetic parameters in vitro and making appropriate corrections for unbound drug concentrations.

Algorithms↗

[Potentiation of the action of reserpine on the frog as a characteristic effect of antidepressants].

Antidepressants-thymoanaleptics chlorimipramine, amitriptyline, imipramine, melitracen potenciated the inhibitory effect of reserpine in a frog (supression of the turning over from the back reflex) stronger than did antidepressants with less marked thymoanaleptic action (Lu-5-003, azaphen, quipazine, desipramine) and also neuroleptics (promazine, stelazine, haloperidol) cholinolytics (atropine and benectyzine) and stimulator--phenamine. The potentiating action of tertiary amines--imipramine, amitriptyline protixen was stronger than that of the corresponding secondary amines (desipramine, norprotixen, nortriptyline). Phenothiazines with the chlorine atom in the second position (chlorprotixen and chlorpromazine) potentiated the effect of reserpine less intensively than did their chlorine-free analogues (protixen, promazine).

Amphetamine↗