Acetaminophen, aspirin, or Ibuprofen in combination analgesic products.

Pain of multiple etiologies remains a substantial problem for many patients presenting in the clinical setting. Improved pain relief can be demonstrated, and adverse effects minimized, by multimodal analgesic combinations as the method to improve pain treatment. Substantial evidence supports combining analgesics for the management of pain and, in some instances, they have a heterogeneous pharmacologic sparing effect. Fixed-dose combination analgesics with demonstrated efficacy and safety are widely useful for pain management. However, work needs to continue to further explore which analgesics at which doses can be combined with a coanalgesic in a patient-specific manner to achieve additive, if not synergistic, multimodal pain relief with the fewest possible adverse consequences. Unsupervised consumption of over-the-counter drugs that contain acetaminophen, aspirin, or ibuprofen offers clinical challenges to both the patient and health care providers. Couple this often undisclosed over-the-counter medication consumption event with prescription medications, which many contain similar combination ingredients, and the potential for a therapeutic misadventure may precipitate. This article will address the safety and efficacy of acetaminophen, aspirin, and ibuprofen independently and in combination with currently available prescription dosage forms with a focus on pharmacology, pharmacotherapeutics, pharmacodynamics, and pharmacokinetics, including drug interactions at the CYP450 system. Patient-specific cautions are presented for opiate/opioid combinations, codeine, hydrocodone, oxycodone, and propoxyphene, and there is a discussion of COX I/COX II agents.

Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia.

Effective management of chronic pain has become an increasingly critical issue in health care. Opioid agonists are among the most effective analgesics available for reducing pain perception; however, their chronic use is controversial. This is primarily due to regulatory barriers, misunderstandings about pain management among primary caregivers, fear of adverse side effects, and misconceptions about the potential risks of addiction. Short-acting opioids provide effective analgesia for acute pain but should be avoided as primary analgesics for chronic pain management. Long-acting opioids have greater utility than short-acting opioids in treating chronic pain in patients with consistent pain levels. Results of studies show that improved quality of life is directly related to the use of long-acting opioids in patients with chronic pain of both cancer and noncancer etiology. Short-acting opioids may be used during the initial dose titration period of long-acting formulations and as rescue medication for episodes of breakthrough pain. Clinical experience reveals that selection of an effective pain regimen for the patient with chronic pain, combined with aggressive management of side effects, leads to improved overall functioning and quality of life.

Recognition and management of depression in primary care: a focus on the elderly. A pharmacotherapeutic overview of the selection process among the traditional and new antidepressants.

Depressed patients consult with their primary care physician before engaging the services of a mental health care provider. Primary care physicians initiate more antidepressant pharmacotherapy than psychiatrists. Major depression has been estimated to have a 5% to 10% prevalence, with up to three times that percentage having significant subsyndromal depression symptoms. Patients frequently deny their depression, often neglecting to recognize their own somatic and cognitive/behavioral subjective symptoms, underestimating symptom severity, and possessing a reluctance to validate their existence because of social stigmata. There remains an underrecognition of the diagnosis of depression by primary care physicians. Often, depressed primary care patients present with somatic symptoms, which include gastrointestinal, skeletal muscle, and cardiovascular complaints, as opposed to describing nonsomatic criteria for depression. Elderly patients presenting with depression have an estimated prevalence of 5% to 50%, and the rate of suicide increases with age. In this patient group, depression may exist independently or secondary to insults or events. Major depressive disorders occur throughout the life cycle; however, the rate of major depression has increased, and the age of onset has become younger. Not uncommonly, complicating psychosocial factors coupled with multiple chronic disease states and physical pathology may mask the diagnosis of depression. Furthermore, up to 25% of extended care facility patients may satisfy the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for depression. Comorbid diseases and pharmacotherapy have been associated with secondary depression. Antidepressant pharmacotherapy combined with cognitive and behavioral therapy appears to offer the most benefit to the patient. Antidepressants independently act as catalysts to facilitate or correct the dysregulation of neurotransmission in depressed patients. The elderly present pharmacotherapeutic challenges based on a changing internal milieu in the absorption, distribution, metabolism, and elimination of most of the antidepressants. Polypharmacy may act to induce or inhibit the metabolism of substrate medication that the patient is currently using. A comprehensive list of cytochrome P450 interactions is provided. Generally the antidepressants display similarity in efficacy; however, effectiveness may be substantially different among and within antidepressant pharmacotherapeutic classes. The pharmacotherapeutic selection of antidepressants is a multifactorial cognitive process, including consideration of medication side effects and adverse effects and patient-specific factors. Other factors in this selection process include drug interaction potential, patient's prior drug response, and both the patient's concomitant pathology and pathophysiology and pharmacotherapy-mediated events. In conjunction with age-related, gender-related, and genetic factors, a full description of current serotonin pharmacotherapy-mediated events is provided. Included in this article are a review of traditional and newer antidepressants, their pharmacokinetics, their pharmacodynamics, and an elaborate interaction focus. Special emphasis is focused on individual antidepressants and class of antidepressants. This article provides comprehensive insights in perception, recognition, treatment, and the selection process involving antidepressants.

The management challenges of chronic pain: the role of antidepressants.

Chronic pain is both difficult for patients to tolerate and for clinicians to treat effectively. It differs from other types of pain in etiology and impact, which in turn affects the duration and modalities of treatment options. Forty years of research have confirmed the efficacy of antidepressant agents in the management of chronic pain, yet these agents are used inadequately. A significant amount of evidence supports the use of the traditional tricyclic antidepressants (TCAs) in the management of chronic pain, but because of their acute synaptic effects on multiple, nontherapeutic receptor systems, they are associated with numerous undesirable side effects. The newer selective serotonin reuptake inhibitors (SSRIs) have, comparatively, only serotonin-receptor-mediated side effects. These agents have not been thoroughly studied in the treatment of chronic pain. Moreover, because SSRIs impact reuptake of only one monoamine system, it is plausible that they may be less efficacious than the TCAs in treating chronic pain. Venlafaxine, the first agent in the new class of serotonin (5-HT)-norepinephrine (NE) reuptake inhibitors, is unique because it inhibits reuptake of both 5-HT and NE (and to a lesser extent dopamine), as do some of the TCAs; however, it accomplishes this without affecting other nontherapeutic receptors. Venlafaxine is at least as effective as the TCAs, but is more tolerable, because it lacks the receptor-mediated side effects common to the TCAs. The unique characteristics of venlafaxine, including minimal cytochrome P-450 drug interaction, may make it a particularly useful antidepressant in the adjunctive treatment of chronic pain.

Analgesics in ophthalmic practice: a review of the oral non-narcotic agent tramadol.

This report reviews the causes of ocular pain and discusses the pharmacology, pharmacokinetics, efficacy, adverse effects, and dosage of tramadol, a novel non-narcotic oral analgesic. Tramadol is a synthetic analog of codeine with a dual mechanism of action that involves agonist activity at the mu opioid receptor, as well as inhibition of monoaminergic (norepinephrine and serotonin) re-uptake. Unlike opiate analgesics, tramadol has very low propensity toward physical dependence. Common dose-related adverse effects of tramadol include dizziness, nausea, vomiting, dry mouth, and/or drowsiness. Clinically, tramadol has been shown to be equivalent to acetaminophen (325 mg)-codeine (30 mg) combinations for the treatment of moderate or severe nonocular pain. Tramadol appears to be an effective analgesic agent for pain control due to postoperative surgical trauma, as well as in various chronic malignant and nonmalignant disease states. Tramadol has shown variable effectiveness in the control of pain related to dental procedures. The usefulness of tramadol in pain states from ophthalmic origin has yet to be clinically established.

Effect of elevated temperature and light on the stability of butorphanol tartrate.

The purpose of this investigation was to determine the short-term stability of butorphanol tartrate in presence of diluents. A 10-mg/mL solution of butorphanol tartrate was diluted to 5 mg/mL using normal saline, 5% dextrose in water (D5W), or sterile water for injection. The diluted solutions were divided into two groups. The effect of temperature was tested by placing one group of sealed amber vials at room temperature and at 37 degrees C. The effect of light was studied by placing a second group in amber and clear vials, then exposing them directly to light. At regular time intervals over a period of 5 weeks, the solutions were analyzed for butorphanol tartrate and degradation products using a high-performance liquid chromatography assay. The concentration of butorphanol tartrate remained practically unchanged, indicating that butorphanol tartrate is not affected by heat or light in the presence of any of the diluents over a period of 5 weeks.

Newer strategies for the treatment of heparin-induced thrombocytopenia.

Treatment with heparin is associated with two types of thrombocytopenia. One is a mild, transient, nonimmune disorder, generally without adverse clinical consequence. The other, known as heparin-induced thrombocytopenia (HIT), is a potentially serious, immunoglobulin-mediated reaction with a paradoxic high risk of thromboembolic events. Various treatment options for HIT are discussed, with emphasis on pharmacologic approaches that control the increased thrombin generation characteristic of this disorder.

A meta-analysis of eight randomized, double-blind, controlled clinical trials of mirtazapine for the treatment of patients with major depression and symptoms of anxiety.

BACKGROUND: Patients diagnosed with major depression and prominent symptoms of anxiety often have a poor prognosis for recovery. A meta-analysis was performed to assess the efficacy of mirtazapine in comparison with placebo and amitriptyline for the relief of anxiety/agitation or anxiety/somatization in patients with major depressive illness. METHOD: A meta-analysis of eight randomized, double-blind, placebo-controlled clinical trials was conducted for 161 mirtazapine-treated and 132 placebo-treated patients with a DSM-III diagnosis of major depression, baseline Hamilton Rating Scale for Depression (HAM-D) scores > or = 18, and a baseline score > or = 6 for the sum of HAM-D items 9, 10, and 11 (anxiety/agitation). Four of the clinical trials included an amitriptyline control group (N = 92). RESULTS: Mirtazapine-treated patients demonstrated a statistically significant (p < or = .05) reduction in the sum of HAM-D items 9, 10, and 11 (anxiety/agitation) compared with placebo-treated patients at Weeks 1, 2, 4, and 6 and at the endpoint. There was no statistically significant difference between the mirtazapine- and amitriptyline-treated patients at Weeks 1, 3, 4, 5, and 6 and at the endpoint. Similar results were found for the analysis of the mean of HAM-D items 10, 11, 12, 13, 15, 17 (anxiety/somatization or HAM-D Factor Score I) using all treated patients with a post-baseline evaluation in all 8 studies. Mirtazapine-treated patients demonstrated a statistically significant (p < or = .03) greater reduction at Weeks 1-6 compared with placebo, and improvement in the mirtazapine group was comparable to improvement in the amitriptyline group at Weeks 1-6. CONCLUSION: In this meta-analysis of eight randomized, double-blind, controlled clinical trials, mirtazapine was found to be superior to placebo and comparable to amitriptyline for the treatment of patients with major depression with symptoms of anxiety/agitation or anxiety/somatization.

Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression.

Mirtazapine is a presynaptic alpha-2 antagonist that has dual action by increasing noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors because mirtazapine is a postsynaptic serotonergic 5-HT2 and 5-HT3 antagonist. In addition, mirtazapine has only a weak affinity for 5-HT1 receptors and has very weak muscarinic anticholinergic and histamine (H1) antagonist properties. As a consequence of its unique pharmacodynamic properties, mirtazapine is an effective, safe and well-tolerated addition to the antidepressant armamentarium. Mirtazapine is well absorbed from the gastrointestinal tract following oral administration, and it is extensively metabolized in the liver to four metabolites via demethylation and hydroxylation, followed by glucuronide conjugation. The unconjugated desmethyl metabolite is pharmacologically less active than the parent compound. Mirtazapine lacks auto-induction of hepatic isoenzymes. Although mirtazapine is a substrate of P450 isoenzymes 1A2, 2D6 and 3A4, in vitro studies show that it is not a potent inhibitor or inducer of any of these enzymes. Mirtazapine has been evaluated in a worldwide clinical development program involving approximately 4500 patients. Controlled clinical trials involving almost 2800 mirtazapine-treated patients have demonstrated the compound to be effective for the treatment of moderate-to-serve major depression. Mirtazapine was consistently superior to placebo, and equivalent in efficacy to the tricyclic antidepressants amitriptyline, doxepin and clomipramine, but with an improved tolerability profile. Mirtazapine has shown a rapid onset of action in patients with predominantly severe depressive illness in a comparative study against fluoxetine. Mirtazapine has a unique tolerability profile, since the specific postsynaptic 5-HT2 and 5-HT3 receptor blockade of mirtazapine provides early antidepressant effects without causing unwanted serotonin-related side-effects. Transient somnolence, hyperphagia and weight gain are the most commonly reported adverse events, which may be attributed to the antihistaminic (H1) activity of mirtazapine at low doses. Somnolence, the most commonly reported side-effect, appears to be less frequent at higher dosages. Mirtazapine also demonstrates important anxiolytic and sleep-improving effects, which may be related to its pharmacodynamic properties. In addition, mirtazapine does not appear to be associated with sexual dysfunction. Mirtazapine has shown no significant cardiovascular adverse effects at multiples of 7 to 22 times the maximum recommended dose. Mirtazapine is a unique addition to the antidepressant armamentarium as first-line therapy in patients with major depression and symptoms of anxiety/agitation or anxiety/somatization or complaints of insomnia and as a useful alternative in depressed patients who do not adequately respond to or are intolerant of tricyclic antidepressants or serotonin-specific reuptake inhibitors.

Efficacy issues with antidepressants.

Clinical trials of antidepressant medications have shown that, overall, these drugs are effective, as measured by a > or = 50% decrease in Hamilton Rating Scale for Depression (HAM-D) total scores in about two thirds of patients. However, the results of long-term trials under rigorously controlled conditions show that, even with close follow-up and provision of interpersonal psychotherapy, a third or more of the patients will not achieve or maintain a response to medication for depression. Nevertheless, the improved efficacy of some antidepressants for certain features or types of depression has been shown. Factors associated with a better response to a specific agent or class of drugs include severity of symptoms, patient age, and the symptom profile of the depressive episode, as revealed by assessment scales or subscale scores for selected symptoms. Moreover, a number of studies indicate that a patient's early response to a given medication may assist in predicting long-term outcome. However, outcome measures in traditional trials of antidepressant drug efficacy, such as a 50% reduction in scores on one or more depression rating scales, do not necessarily reflect an improvement in the patient's ability to function in the workplace; they only show that a particular patient at a particular time has responded to treatment in a significant manner by measurement of a depression scale.

Management of chronic pain. Part II.

Chronic pain is associated with substantial psychosocial and economic stress coupled with functional loss and various levels of vocational dysfunction. The role of a pain center is to focus on chronic pain in a multidisciplinary, comprehensive manner, providing the patient with the most effective opportunity to manage his or her chronic disease syndrome. This article focuses on methods to manage many types of chronic pain and describes a broad range of pharmacologic and non-pharmacologic interventions and options available to the patient. Part I of this two-part monograph described pharmacotherapeutic interventions and regional nerve blocks. Part II focuses on psychologic assessment and treatment and physical therapy. A multimodal management strategy offers patients the greatest improvement potential for specific chronic pain syndromes. Cognitive and behavioral therapies and physical therapies are described. This combination of therapies may provide patients with the skills and knowledge needed to increase their sense of control over pain. The integration of appropriate pharmacotherapeutic regimens, neural blockades, physical therapy, and psychologic techniques maximizes the patient's effectiveness in dealing with chronic pain. Three case studies are presented in Part II.

Management of chronic pain. Part I.

Chronic pain is associated with substantial psychosocial and economic stress, coupled with functional loss and various levels of vocational dysfunction. The role of a pain center is to focus on chronic pain in a multidisciplinary, comprehensive manner, providing the patient with the most effective opportunity to manage his or her chronic disease syndrome. This article focuses on methods to manage many types of chronic pain and describes a broad range of pharmacologic and nonpharmacologic interventions and options available to the patient. Part I of this two-part monograph describes pharmacotherapeutic interventions and regional nerve blocks. Part II focuses on psychologic assessment and treatment and physical therapy. A multimodal management strategy offers patients the greatest improvement potential for specific chronic pain syndromes. Cognitive and behavioral therapies and physical therapies are described. This combination of therapies may provide patients with the skills and knowledge needed to increase their sense of control over pain. The integration of appropriate pharmacotherapeutic regimens, neural blockades, physical therapy, and psychologic techniques maximizes a patient's effectiveness in dealing with chronic pain. Three case studies are presented in Part II.

Recognition, assessment, and treatment of anxiety in the critical care patient.

A multidisciplinary group of experts involved in the treatment of critically ill patients participated in a workshop conference designed to develop practice recommendations for the recognition, assessment, and treatment of anxiety in the critical care environment. Anxiety was identified as a ubiquitous problem in critical care that may interfere with healing and recovery. The faculty agreed that clinicians should be familiar with the signs and symptoms of anxiety and should be able to determine when interventions are necessary. Whenever possible, nonpharmacologic methods for anxiolysis should be incorporated into intensive care protocols. Intensive care personnel should be trained in those interventions that require specialized expertise, and they should become familiar with the drugs available for the treatment of anxiety. Protocols for determining the best agents to be used in a given setting and their most appropriate method of administration should be established. Pharmacologic and nonpharmacologic treatments are not mutually exclusive but should be complementary. Finally, procedures for obtaining psychiatric consultation, when necessary, should be in place.