Robert L. Barkin

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.

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.

Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult?

The prevalence of chronic pain increases with age, exceeding 50% in individuals aged ≥65 years. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay of chronic pain management but carry significant dose-related risks of cardiovascular, renal, haematological and other systemic adverse events (AEs). Older patients have an increased risk of these AEs and are more likely to take multiple medications that can potentially interact with NSAIDs. In particular, older patients are more likely to have cardiovascular disease and a natural age-related decline in renal function, increasing the risks of cardiovascular, haematological and renal AEs. Given these risks, recent guidelines for the management of chronic pain in the elderly recommend using NSAIDs rarely and only in carefully selected patients. NSAIDs currently available in the US fall into three categories: nonselective NSAIDs that act via inhibition of cyclo-oxygenase (COX)-1 and COX-2; celecoxib, a selective inhibitor of COX-2; and topical NSAIDs that inhibit both COX-1 and COX-2 but result in much less systemic NSAID exposure than oral formulations. Topical NSAIDs have demonstrated efficacy similar to oral NSAIDs, with an incidence of AEs similar to placebo; however, these agents are an option only in patients with localized pain in superficial joints. Safe pain management in older patients therefore requires cautious choice of selective and nonselective oral NSAIDs, topical NSAIDs or non-NSAID analgesics. This article discusses the risks and benefits of NSAID therapy, reviews its mechanism of action as the source of adverse effects and provides recommendations for maximizing NSAID safety, particularly in older patients. Articles cited in this review were identified via a search of PubMed (January 2005 to November 2009) and a manual search of reference lists from the articles identified in that search. Priority was given to articles discussing NSAID use in older populations, clinical trials of high quality, reports on NSAID safety and AEs, and treatment guidelines.

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 heterogenous 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.

Sublingual buprenorphine is effective in the treatment of chronic pain syndrome

Many patients with chronic pain have less than optimal therapeutic outcomes after prolonged treatment with opiate analgesics. Worsening of pain perception, functional capacity, and mood often result. Medical detoxification is often undertaken in this situation. Ninety-five consecutive patients (49 men and 46 women; age range, 26-84) with chronic noncancer pain (maldynia) were referred by local pain clinics for detoxification from long-term opiate analgesic (LTOA) therapy. All patients had failed treatment as manifest by increasing pain levels, worsening functional capacity, and, in 8%, the emergence of opiate addiction. Length of prior LTOA therapy ranged from 1.5 to 27 years (mean, 8.8 years). After a minimum of 12 hours of abstinence from all opiate analgesics, patients were given low doses of sublingual (SL) buprenorphine or buprenorphine/naloxone (Reckitt Benckiser). Maintenance dosing was individualized to treat chronic pain. Daily SL dose of buprenorphine ranged from 4 to 16 mg (mean, 8 mg) in divided doses. Mean duration of treatment is 8.8 months (range, 2.4-16.6 months). At clinic appointments, patients were assessed for pain reports, functional capacity, and mood inventory. Eighty-six percent of patients experienced moderate to substantial relief of pain accompanied by both improved mood and functioning. Patient and family satisfaction was robust. Only 6 patients discontinued therapy secondary to side effects and/or exacerbation of pain. In this open-label study, SL buprenorphine and buprenorphine/naloxone were well tolerated and safe and appeared to be effective in the treatment of chronic pain patients refractory to LTOA.

Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder

BackgroundThis was an open-label, single-center study of the long-term efficacy and effectiveness of venlafaxine extended release (XR) in the treatment of chronic pain and depression in outpatients. All patients have been diagnosed with major depressive disorder (MDD) of various types, with or without chronic pain, and had previously failed treatment with either tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). MethodsEfficacy of treatment was determined using the 21-item Hamilton Rating Scale for Depression (HAMD-21), the Visual Analogue Scale (VAS) for the evaluation of pain, and a 12-item quality of life scale (QOL). Patients were treated in an unblended open trial for 1 year with 150 mg or more of venlafaxine XR once daily. ResultsAfter 1 year of treatment, 21-item Hamilton Rating Scale for Depression, Visual Analogue Scale, and quality of life scores were significantly improved from permanent baseline scores. ConclusionThese data show long-term efficacy and effectiveness of venlafaxine XR, a serotonin (5-HT) and norepinephrine (NE) and dopamine (DA) reuptake inhibitor antidepressant agent, having analgesic properties.

Anticholinergic syndrome after anesthesia: a case report and review.

Anticholinergic syndrome may present with a wide variety of signs and symptoms. Central manifestations range from excitatory symptoms including delirium and agitation to central nervous system depression, stupor and coma. Anticholinergic syndrome was once a common phenomenon after general anesthesia because of the frequent administration of the anticholinergic agents atropine and scopolamine. Now that these agents are rarely administered, anesthesia-related anticholinergic syndrome is currently infrequently reported. Still, many prescription and over the counter medications as well as many anesthetic agents possess anticholinergic activity, and this diagnosis should be considered in patients with altered mental status following general anesthesia. We report a case of prolonged somnolence following general anesthesia for an MRI. A rapid improvement of mental status with physostigmine confirmed the diagnosis of anticholinergic syndrome. This case is unique in that anticholinergic syndrome-related respiratory depression was promptly reversed with physostigmine.

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.

A clinical and pharmacologic review of skeletal muscle relaxants for musculoskeletal conditions.

Muscle strains and other musculoskeletal disorders (MSDs) are a leading cause of work absenteeism. Muscle pain, spasm, swelling, and inflammation are symptomatic of strains. The precise relationship between musculoskeletal pain and spasm is not well understood. The dictum that pain induces spasm, which causes more pain, is not substantiated by critical analysis. The painful muscle may not show EMG activity, and when there is, the timing and intensity often do not correlate with the pain. Clinical and physiologic studies show that pain tends to inhibit rather than facilitate reflex contractile activity. The decision to treat and choice of therapy are largely dictated by the duration, severity of symptoms, and degree of dysfunction. Trigger point injections are sometimes used with excellent results in the treatment of muscle spasm in myofacial pain and low-back pain. NSAIDs are used with much greater frequency than oral skeletal muscle relaxants (SMRs) or opioids in the treatment of acute MSDs. Unfortunately, remarkably little sound science guides the choice of drug for the treatment of acute, uncomplicated MSDs, and the evaluation of efficacy of one agent over another is complicated by numerous factors. Only a limited number of high-quality, randomized, controlled trials (RCTs) provide evidence of the effectiveness of NSAIDs or SMRs in the treatment of acute, uncomplicated MSDs. The quality of design, execution, and reporting of trials for the treatment of MSDs needs to be improved. The combination of an SMR and an NSAID or COX-2 inhibitor or the combination of SMR and tramadol/acetaminophen is superior to single agents alone.

Focus on the COX-1 and COX-2 agents: Renal events of nonsteroidal and anti-inflammatory drugs-NSAIDs

This article will focus upon some of the cautions used in the process of prescribing NSAIDs with a focus upon renal events, pharmacokinetics of COX-2 agents, and phytopharmaceuticals that present co-prescribing hematologic challenges. Prescribing any pharmacotherapeutic agent presents the clinician with the cognitive challenge between providing a therapeutic balance weighing potential benefits to be achieved through prescribing against the potential liabilities of pharmacokinetic and pharmacodynamic iatrogenic events, and drug interactions. The following information is presented as a brief overview of the familiar arachidonic acid cascade followed by the renal events reported with non-COX-2-specific NSAIDs. The pharmacokinetics of the three currently available COX-2 NSAIDs are presented. Patient-specific risk assessments for renal function/dysfunction should be considered prior to or concurrent with initiation of any NSAID therapy coupled with periodic renal monitoring during treatment of those with patient risk factors. Phytopharmaceuticals, supplements, and over-the-counter agents should be discussed with the patient following patient disclosure of use and not omitted by the patient during presentation of their medication consumption with utilization history to their respective healthcare professionals.