Abstract
Psychiatric disorders play a critical role in the experience of pain and the development of chronic pain syndromes. About 60% to 80% of patients referred to pain clinics have significant psychiatric pathology and frequently present with prescribed psychoactive medications. This comorbidity worsens their pain and disability, and their mental illness is an independent source of suffering, further reducing their quality of life. Many of the psychotherapeutic medications also have independent analgesic properties and are a mainstay of the drug armamentarium of the pain physician. Antidepressants, anticonvulsants, and antipsychotics are the most notable for their pain properties. This chapter provides a focused overview on the use of psychotherapeutic medications as they pertain to treating patients with pain and psychiatric comorbidity. The improved treatment results for psychopathology and the emergence of additional analgesics have been extremely helpful to the practice of pain medicine.
Keywords
anticonvulsants, antidepressants, mood stabilizers, neuroleptics, psychiatric comorbidity, psychopharmacology
Burgeoning evidence suggests that psychiatric factors play a critical role in the experience of pain and the development of chronic pain syndromes. One of the early studies that described this phenomenon was performed by Atkinson et al. at the Veterans Affairs Medical Center Low Back Pain Clinic. They studied 100 consecutive admissions to the clinic and compared lifetime and current rates of depression, alcohol abuse, and anxiety between controls and the chronic back pain cohort. The 6-month and lifetime rates of major depression were 22% and 32%, respectively, versus 6% and 16% for controls. Subsequent to the onset of pain, patients had a relative risk of 9.0 for developing major depression. The lifetime alcohol abuse rate for chronic pain patients was 65%, compared with 39% for controls. Patients with pain and psychiatric comorbidity are commonly referred to pain medicine clinics and frequently present with prescribed psychoactive medications. Many of these medications, such as antidepressants and anticonvulsants, also have analgesic properties and are a mainstay of the drug armamentarium of the pain physician. Consequently it behooves the astute pain practitioner to be familiar with the psychiatric comorbidities of patients with chronic pain and to understand the therapeutic benefits and risks associated with the use of psychoactive medications to treat both pain and/or psychopathology. Psychotherapeutic modalities, such as cognitive behavioral therapy, relaxation training, and biofeedback, play an important role in the treatment of both psychiatric and chronic pain syndromes; in some cases they are the preferred method of treatment. However, this chapter focuses on the use of medications as they pertain to treating patients with pain and psychiatric comorbidity. As with many of the medications used in pain medicine, psychoactive medications with reported analgesic properties do not always have an indication from the US Food and Drug Administration (FDA) for this purpose, but they can legally be prescribed for off-label use.
Epidemiology
Over three decades, studies of US pain clinic populations have shown that by the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM), 60% to 80% of these patients have psychiatric illnesses. Estimates are lower for persons with pain in primary care, institutional, and community settings, but regardless of setting, given the prevalence of persistent pain in adults, which is estimated at 20% to 45%, pain combined with psychiatric comorbidity constitutes an important public health problem. Patients with psychiatric illness report greater pain intensity, more pain-related disability, and a larger affective component to their pain. The majority of patients with psychiatric comorbidity developed their psychiatric illness after the onset of chronic pain. Major depression alone affects 30% to 50% of all pain clinic patients, followed by anxiety disorders, personality disorders, somatoform disorders, and substance use disorders. Virtually all psychiatric conditions can be treated with variable improvement and the majority of patients who are provided with appropriate treatment show significant improvement. Of the disorders that most frequently affect patients with chronic pain, major depression and anxiety disorders are the most common and have the best response to medication. Regardless of the specific psychopathology, however, improvement in psychiatric illness results in diminished pain levels, greater acceptance of the chronicity of pain, improved functionality, and improved quality of life. Although this chapter focuses on psychopharmacologic treatment, it is important to note that in general combined pharmacologic and psychotherapeutic treatments are more effective in alleviating depression and anxiety than pharmacologic treatment alone. Psychotherapeutic treatments (e.g., cognitive-behavioral therapies, relaxation and biofeedback, interpersonal therapies, and group therapies) are covered in other chapters of this book.
Psychiatric Nosology
Mental health practitioners utilize the fifth edition of the DSM (DSM-5) or the tenth revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) as an aid in making psychiatric diagnoses. Although these manuals outline the suggested criteria for psychiatric diagnosis elegantly, they are not very good at highlighting which symptoms are more or less important in making a diagnosis. Although the criteria have high reliability—that is, two psychiatrists applying the criteria to the assessment of the same patient will very often come up with the same diagnosis—the criteria do not all have equally high validity. That is, there is no universal agreement that the symptoms listed under diagnostic criteria for a particular condition are the best description of that illness. In this light, and in an attempt to demystify psychiatric diagnosis for the pain physician, the following descriptions of psychopathology emphasize the hallmark features of each illness.
Major Depression and Subthreshold Depression
Symptoms: According to the DSM-5, major depressive disorder (MDD) requires the presence of depressed mood and loss of interest or pleasure in most activities (anhedonia) for at least 2 weeks. The lifetime risk of MDD is 7% to 12% in men and from 20% to 25% in women. But the risk of major depression in patients with pain is at least twice as high. As the most prevalent of the psychiatric comorbidities, major depression can be distinguished from situational depression (also termed demoralization or adjustment disorder with depressed mood ) by the triad of persistently low mood, self-attitude changes, and changes in vital sense, all lasting at least 2 weeks. Low mood manifests itself by emotions of “feeling blue,” down, or depressed. Anhedonia, or the inability to experience pleasure, is a key reflection of low mood. A diminished self-attitude is seen in feelings of guilt or thinking that one is a bad person. Changes in vital sense means changes in sleep, appetite, or energy level. Patients with major depression often feel that their thinking is slow or fuzzy, and they have difficulty concentrating. Depressed patients may feel anxious, have panic attacks, or experience symptoms of posttraumatic stress disorder (PTSD), which, if they occur in the presence of significant depression, are consistent with an MDD and not a separate anxiety disorder. Depressive symptoms may present as Beck triad, with patients feeling hopeless, hapless, and helpless. They see the future as bleak; they feel that they cannot help themselves and that no one else can help them. Suicidal thoughts reflect the severity of depressive symptoms. Untreated or undertreated major depression has a lifetime risk of death through completion of suicide of 10% to 15%. Major depression is a serious complication of persistent pain; if not treated adequately, it will reduce the effectiveness of all pain treatment. Even low levels of depression (“subthreshold depression”) may worsen the physical impairment associated with chronic pain conditions and should also be treated.
Treatment
Antidepressants can take up to 2 to 4 weeks to produce an initial response, but all can take 4 to 8 weeks for full clinical improvement after a typical dose is reached, and remission may take longer. This can be particularly the case for depressed patients who also suffer from comorbid pain. Patients should remain on their medications for 6 to 12 months for the treatment of an initial depressive episode and for 5 years for the treatment of a recurrent depressive episode. Regardless of the medication chosen, approximately 60% of patients will respond (have at least a 50% improvement) to the initial antidepressant prescribed. At least 80% of patients will respond to at least one medication, either with or without an augmentation agent such as lithium, an anticonvulsant, or another antidepressant. There is some evidence that pain patients with major depression have increased treatment resistance, particularly when their pain is not effectively managed. Older adults tend to respond at lower doses of antidepressants, and dose titration should occur more slowly in this group because of their heightened sensitivity to side effects and toxicity. A good rule of thumb in starting antidepressants in any age group is to begin with one quarter to one half of the standard initial treatment dose for a week and then advance gradually over the next 2 to 3 weeks to the treatment dose. This minimizes side effects and increases treatment compliance.
Often, patients with chronic pain are on multiple medications that can potentiate the side effects of antidepressants, such as headache, nausea, constipation, or sedation; therefore “starting low and going slow” is even more important in this population. Typically, in the initial treating period, reevaluations are done every 2 to 4 weeks, with dose adjustments if indicated. Monoamine oxidase inhibitors (MAOIs), such as phenelzine, which are rarely prescribed any longer, should not be prescribed concurrently with other antidepressants. Because of the inherent risks of these medications, they should be used only by experienced psychopharmacologists.
Cognitive-behavioral therapy (CBT) in conjunction with antidepressant therapy is the most efficacious treatment for major depression. CBT examines negative and destructive thoughts that arise in conjunction with low moods, helping patients to see the unrealistic and maladaptive qualities of thoughts and behaviors.
Selective Serotonin Reuptake Inhibitors
Since the introduction of fluoxetine (Prozac) in 1987, many selective serotonin reuptake inhibitors (SSRIs) have been introduced. They have an immediate effect on the blockade of the presynaptic serotonin reuptake pump in the central nervous system (CNS), which has been shown in animals to increase the duration of serotonin in the synaptic cleft, increasing the effects of neurotransmission. The antidepressant efficacy of SSRIs and their low side-effect profiles have made them the most widely prescribed class of antidepressants. However, the SSRIs have few independent pain properties. Pain patients whose depression responds to an SSRI may have diminished pain that is attributable to improvements in the affective components of their pain, but there is little evidence supporting independent analgesic activity of SSRIs. Although a few case reports have shown improvements in diabetic neuropathic pain treated with SSRIs, double-blind, placebo-controlled clinical trials that exclude patients with depression have not consistently demonstrated analgesic benefit.
Before prescribing an SSRI, all medications/supplements that the patient is taking must be carefully reviewed along with their general medical condition, since SSRIs are commonly associated with easy bruising/bleeding and osteoporosis. SSRIs can cause serotonin syndrome when given with other medications, including serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), MAOIs, triptans (e.g., sumatriptan), and antiemetics (e.g., ondansetron, metoclopramide). Moreover, serotonin syndrome can be precipitated by a combination of SSRIs and multiple analgesics, including tramadol, meperidine, fentanyl, and pentazocine. The use of SSRIs in combination with tramadol can lower the seizure threshold, and caution is called for if these drugs are combined. No additional laboratory workup is required in starting SSRIs, and dose titration is based on clinical response and side effects. Fluoxetine tends to be more activating and is prescribed in the morning, whereas paroxetine, with its anticholinergic effect of activating muscarinic receptors, is more sedating and has greater anxiolytic properties. It is generally prescribed in the evening. Paroxetine has a relatively shorter half-life than most SSRIs and is often associated with withdrawal symptoms upon discontinuation. Sertraline and citalopram tend to be less sedating than paroxetine and are generally prescribed in the morning.
Patients should begin on half of the usual dose for a week ( Table 48.1 ) and then go on to the standard dose so as to minimize the side effects of nausea, diarrhea, tremor, and headache. Some patients can experience sedation or overstimulation. Approximately 75% to 80% of patients on SSRIs can experience sexual side effects, such as decreased libido, impotence, ejaculatory disturbances, or anorgasmia. This can be particularly the case in elderly patients who may already have diminished libido owing to possible comorbid pain and depression. Rare side effects include dystonia, akathisia, palpitations, a lowered seizure threshold, serotonin syndrome, or the syndrome of inappropriate antidiuretic hormone (SIADH).
| Drug | Usual Start Dose | Average Dose | Maximum Dose |
|---|---|---|---|
| Citalopram (Celexa) | 10 mg qd | 20–40 mg qd | 60 mg/day |
| Fluoxetine (Prozac) | 10 mg qd | 20–40 mg qd | 80 mg/day |
| Fluvoxamine (Luvox) | 25 mg qd | 50–100 mg bid | 300 mg/day |
| Paroxetine (Paxil) | 5–10 mg qd | 20–40 mg qd | 60 mg/day |
| Sertraline (Zoloft) | 25 mg qd | 50–150 mg qd | 200 mg/day |
SSRIs are metabolized by hepatic oxidation, and their use may alter the serum levels of other hepatically metabolized drugs. SSRIs induce and/or inhibit various cytochrome P450 (CYP450) enzymes. Most significantly, they can increase levels of TCAs and benzodiazepines (BZDs). They may also affect levels of carbamazepine, lithium, antipsychotics, and commonly used analgesics, such as methadone, oxycodone, and fentanyl. Fluoxetine, paroxetine, and to a lesser extent fluvoxamine are inhibitors of cytochrome 2D6; fluoxetine and fluvoxamine also interfere with cytochrome 3A4. There is also evidence that sertraline at doses greater than 100 mg may inhibit these enzymes and thus may increase the circulating metabolites of certain opioids. Citalopram and escitalopram have less of an effect on CYP450 enzyme activity. If taken in overdose, SSRIs are rarely, if ever, lethal. In discontinuing SSRIs, they should be tapered down slowly to avoid a withdrawal syndrome, which has the same symptoms as initiation of SSRIs (headache, nausea, diarrhea, or myalgias).
Tricyclic Antidepressants
TCAs are one of the oldest classes of antidepressants and they act by inhibiting both serotonergic and noradrenergic reuptake. This lengthens the time serotonin and norepinephrine (NE) remain in the synaptic cleft, enhancing their neurotransmission. The analgesic properties of TCAs are independent of their treatment effects on depression, thus making them a good choice for treating depression in patients with chronic pain, particularly if cost is a factor.
All TCAs are equally effective for the treatment of depression; the choice of a particular one is determined by side effects. The magnitude of anticholinergic and antihistaminic effects is the largest determinant. Amitriptyline and imipramine are more sedating, with more weight gain and orthostatic hypotension. Other anticholinergic side effects include dry mouth, constipation, blurred vision, urinary retention, sexual side effects, excessive sweating, and confusion or delirium. TCAs also decrease the seizure threshold. Desipramine and nortriptyline have fewer anticholinergic side effects, and of all of the TCAs, desipramine has the fewest anticholinergic side effects. Serum plasma levels can be monitored for TCAs, and this is particularly important for desipramine, imipramine, and nortriptyline, which have the best correlation of blood levels to therapeutic antidepressant response. The therapeutic blood level for nortriptyline ranges from 50 to 150 ng/mL; it is 75 to 225 ng/mL for both desipramine and imipramine, as desipramine is simply the desmethyl metabolite of imipramine.
Prior to initiating treatment, patients should have laboratory screening of electrolytes, blood urea nitrogen (BUN), and creatinine as well as liver function tests (LFTs). TCAs also have quinidine-like properties, are potentially proarrythmic, and can prolong the QTC interval. It is recommended that patients with a history of cardiac disease or who are taking other QTC-prolonging medications have a baseline electrocardiogram (EKG), with particular attention to the QTC interval. TCAs are strongly protein-bound (85%–95%) and undergo first-pass hepatic metabolism. Subsequent stages involve demethylation, oxidation, and glucuronide conjugation. Amitriptyline is demethylated to nortriptyline, and imipramine is demethylated to desipramine. Hepatic clearance involves the P450 enzyme system, so drugs such as SSRIs, cimetidine, and methylphenidate can increase TCA plasma levels. SSRIs and TCAs should not be prescribed at the same time unless plasma levels are carefully monitored. Phenobarbital, carbamazepine, and cigarette smoking induce the P450 enzyme system and thus decrease serum TCA levels.
As with SSRIs, to minimize side effects and increase adherence, initiation of TCAs should begin at lower doses (usually 25 mg for a week) than the target doses for antidepressant effect (typically 75 to 150 mg) ( Table 48.2 ). The elderly are more sensitive to their side effects, and many psychiatrists begin at doses of 10 to 20 mg in this age group. With diminished or altered metabolism of TCAs, as well as the multiple medications older patients are frequently taking, they are more prone to develop toxic serum levels, and monitoring should be more frequent. There is a withdrawal syndrome with abrupt discontinuation of TCAs, characterized by fever, sweating, headaches, nausea, dizziness, and/or akathisia. Unlike the SSRIs, overdose can be lethal. TCA overdose is a leading cause of drug-related overdose and death. Three to five times the therapeutic dose is potentially lethal, so this narrow therapeutic range must be respected, and serial blood levels monitored. Toxicity results from anticholinergic and proarrythmic effects such as seizures, coma, and QTC widening.
| Drug | Usual Start Dose | Average Dose | Maximum Dose |
|---|---|---|---|
| Amitriptyline (Elavil) | 10–25 mg qd | 75–150 mg qd | 300 mg/day |
| Amoxapine (Asendin) | 25 mg bid | 75–200 mg bid | 600 mg/day |
| Clomipramine (Anafranil) | 25 mg qd | 150–250 mg qd | 250 mg/day |
| Desipramine (Norpramin) | 10–25 mg qd | 75–150 mg qd | 300 mg qd |
| Doxepin (Sinequan) | 10–25 mg qd | 75–150 mg qd | 300 mg qd |
| Nortriptyline (Pamelor) | 10–25 mg qd | 75–150 mg qd | 200 mg qd |
| Protriptyline (Vivactil) | 5 mg qd | 10 mg tid | 60 mg/day |
Also, unlike the SSRIs, TCAs have independent analgesic properties. A series of studies by Max and others have illustrated the analgesic properties of TCAs, which are independent of its effects on improving depression. TCAs have been shown to be modestly effective for diabetic neuropathy pain, chronic regional pain syndrome, chronic headache, poststroke pain, and radicular pain. Additionally, TCAs are useful as preemptive analgesics, being opioid-sparing in the postoperative period. Although the initial studies were done with amitriptyline and desipramine, subsequent studies have confirmed that the other TCAs have equivalent analgesic properties. Of note, the typical doses for the analgesic benefit of TCAs (25 to 75 mg) are lower than the typical doses for antidepressant effect (75 to 150 mg). However, many patients are referred to a pain specialist after a failed trial of TCAs at lower doses. And yet there is a dose–response relationship for analgesia. So even if one is using a TCA solely for pain relief, patients may benefit with a dose in the antidepressant range in conjunction with blood level monitoring.
Serotonin-Norepinephrine Reuptake Inhibitors
The nontricyclic SNRIs are a newer group of antidepressants that, like the TCAs, act by inhibiting serotonin and NE reuptake. This appears to be one of the mechanisms accounting both for the higher rates of depression remission and the analgesic efficacy associated with TCAs and SNRIs as compared with SSRIs. Venlafaxine, desvenlafaxine, duloxetine, and milnacipran are the main drugs in this category. They have significantly less alpha-1, cholinergic, and histamine inhibition and thus fewer side effects than the tricyclics, with equivalent antidepressant and potentially equal analgesic benefits. Placebo-controlled studies have demonstrated modest efficacy in neuropathic pain for both venlafaxine and duloxetine. A numbers-needed-to-treat analysis suggested superior analgesic properties of TCAs (particularly amitriptiline), which may be due to their properties of N -methyl- d -aspartic acid (NMDA) antagonism and sodium channel blockade in addition to their combined SNRI effect.
Venlafaxine is given in two or three divided daily doses (even with extended-release formulations), beginning at 37.5 mg/day for a week and then slowly increased to as high as 375 mg/day ( Table 48.3 ). A typical dose is 150 to 225 mg/day. Generally patients are escalated over a month to 75 mg/day; then, depending on clinical response, the dose is adjusted.
| Drug | Usual Start Dose | Average Dose | Maximum Dose |
|---|---|---|---|
| Bupropion (Wellbutrin) | 75 mg bid | 100–150 mg bid | 600 mg qd |
| Duloxetine (Cymbalta) | 30 mg qd | 60 mg qd | 120 mg |
| Mirtazepine (Remuron) | 15 mg qhs | 30–45 mg qd | 60 mg qd |
| Nefazodone (Serozone) | 100 mg bid | 150–300 mg bid | 600 mg/day |
| Trazodone (Desyrel) | 50 mg qhs | 150–250 mg bid | 600 mg/day |
| Venlafaxine (Effexor) | 37.5 mg qd | 75–112.5 mg bid | 375 mg/day |
Laboratory studies are not needed prior to starting venlafaxine, but patients with hypertension should be treated with caution. Particularly at doses over 150 mg/day, venlafaxine may increase systolic blood pressure by 10 mm or more. This is likely due to the onset of NE reuptake inhibition, which occurs at the higher doses of venlafaxine that appear to be needed for analgesic efficacy in neuropathic pain, unlike tricyclics, which may be effective at lower than antidepressant doses. Other side effects include nausea, somnolence, dry mouth, dizziness, nervousness, constipation, anorexia, and/or sexual dysfunction. Venlafaxine may affect hepatic metabolism of other medications, but it is a weak inhibitor of the CYP450 system.
Venlafaxine (Effexor) is structurally similar to tramadol; in mice, venlafaxine demonstrates opioid-mediated analgesia that is reversed by naloxone. Both controlled studies and case reports indicate that venlafaxine has analgesic properties independent of its antidepressant effects in a variety of neuropathic conditions. Many patients are unable to tolerate the side effects of tricyclics, so venlafaxine and duloxetine are promising agents in patients with major depression and chronic pain. Desvenlafaxine (Pristiq) is the active metabolite of venlafaxine and was recently approved by the FDA for the treatment of MDD. Preliminary studies have shown success in treating neuropathic pain at higher doses. It is classified as a combined serotonin (5-HT) and NE reuptake inhibitor (SNRI) but also inhibits the reuptake of dopamine to a lesser degree. Unlike venlafaxine, the affinity of desvenlafaxine for the 5-HT and NE receptors does not increase with escalating doses of the medication. An initial dose of 50 mg/day is recommended that can be titrated up to 100 mg/day for treatment of depression. However, higher doses up to 400 mg/day have shown some efficacy in treating neuropathic pain. Venlafaxine was shown to be as effective at treating painful polyneuropathy as imipramine in a recent randomized study.
Duloxetine (Cymbalta) is an SNRI approved for use in the United States for diabetic peripheral neuropathy, fibromyalgia, major depression, and generalized anxiety disorder. It is the only major psychotropic drug approved in the United States for both pain and psychiatric conditions; thus it is the treatment of choice for patients with neuropathic pain and psychiatric comorbidity. The typical starting dose is 30 mg at dinnertime for a week, then increasing to 60 mg at dinnertime. Dosing in the evening tends to mitigate the side effects of nausea and tiredness. Other side effects include dry mouth, dizziness, constipation, and sexual dysfunction. Dosing in the elderly should begin lower, at about 20 mg/day, because of increased side effects and less tolerability in these patients. The maximum dose that has been studied is 120 mg/day. Most of the studies show no significant benefit above doses of 60 mg/day, but there is a range of individual responses and some patients will preferentially respond at the higher dose. Duloxetine is a moderate inhibitor of the CYP2D6 liver enzyme and thus may increase TCA and antipsychotic levels. No laboratory tests are needed prior to prescribing duloxetine. It should not be prescribed to patients with renal or liver insufficiency.
Milnacipran (Savella): In the United States, milnacipran is FDA-approved for the treatment of fibromyalgia but not depression. However, in Europe, milnacipran has an established use for both chronic pain and depression. It is an SNRI that has shown some efficacy in treating neuropathic pain and fibromyalgia at a dose of 100 mg to 200 mg/day. A recent Cochrane systematic review indicates that milnacipran provides at least a 30% reduction in pain caused by fibromyalgia for 40% of patients compared with a similar level of pain relief in 30% of patients given placebo. There was insufficient evidence to evaluate a higher threshold of pain relief (50%) and there were no data to support its use in other neuropathic pain conditions. The magnitude of the effect is relatively modest but it may be clinically significant, since fibromyalgia has been extremely difficult to treat. Adverse events were more often associated with the dose of 200 mg/day than with that of 100 mg/day, with a number needed to harm of 23 and a number needed to treat of 8.8. Nausea and constipation were the most common events reported with this treatment regimen. The mechanism of action is not fully understood, but it is theorized to be involved in the modulation of endogenous analgesic mechanisms via descending inhibitory pathways. The increase in serotonin and NE with milnacipran augments the inhibition of painful signals, resulting in a reduction of pain intensity.
Other Antidepressants
Bupropion (Wellbutrin) is a noradrenergic and dopaminergic reuptake pump inhibitor, prolonging the time that NE and dopamine remain in the synaptic cleft. Unlike many of the other antidepressants, it has significant psychostimulant properties. It is used in the treatment of depression, attention deficit hyperactivity disorder (ADHD), and smoking cessation at doses up to 600 mg/day (see Table 48.3 ). Studies have shown that bupropion has independent analgesic effects in a variety of neuropathic conditions. Anecdotal reports have also indicated that bupropion is effective in alleviating the sedative effects of opioids. Consequently bupropion has an important use in pain medicine. Enthusiasm was dampened, however, by a randomized controlled trial (RCT) in 44 patients with chronic low back pain showing no significant improvement.
Treatment with bupropion should start at 75 to 100 mg in the morning to avoid insomnia, which may occur if the drug is started at night. After 5 days, this dose is advanced to the average treatment dose of 100 to 150 mg bid, even for sustained-release preparations. At these doses there is a very slight decrease in seizure threshold. Doses from 450 to 600 mg/day may cause seizures in 4% of patients, so these doses should be avoided. Bupropion should not be prescribed to patients with seizures, eating disorders, or those taking MAOIs. Caution is needed in coprescribing bupropion with tramadol, since lowering of the seizure threshold is most likely additive. Side effects include nervousness, headache, irritability, and insomnia.
Mirtazapine is an antidepressant with antagonism of serotonin and central presynaptic alpha-2 adrenergic receptors, stimulating serotonin and NE release. This serves to potentiate serotonergic and noradrenergic transmission while having no anticholinergic effects. It is thought to preferentially augment serotonergic transmission and have an antihistaminic effect at lower doses of 15 to 30 mg/day. At higher doses, 45 to 60 mg/day, it augments more noradrenergic transmission (see Table 48.3 ). As a result, at lower doses it is more sedating and has antianxiety effects, with the side effect of weight gain. At higher doses it is more activating and can provoke anxiety symptoms. Agranulocytosis and neurotropenia can rarely occur with this medication at an incidence of 0.3%. One case report and an open-label study indicate that there may be analgesic benefits to mirtazapine, but improvements in depression were not adequately controlled.
Trazodone, like nefazodone, is a serotonin-2 antagonist/reuptake inhibitor (SARI) used to treat major depression and insomnia. The sedative qualities of trazodone are so great that few patients are able to get to a dose that is high enough to be in the effective antidepressant range. Trazodone is most often prescribed for insomnia accompanying symptoms of depression, anxiety, or pain and is the preferred treatment of many pain physicians for insomnia. Typical dosing for sleep is 25 to 100 mg at bedtime (see Table 48.3 ). For depression, dosing for trazodone and nefazodone is 50 to 600 mg/day in two divided doses. A rare but serious side effect of trazodone is priapism, occurring in 1 in 1000 to 1 in 10,000 cases. Side effects common to both medications are sedation, dizziness, dry mouth, orthostatic hypotension, constipation, and headache. Studies have shown that trazodone has few analgesic properties. No such studies have been done with nefazodone, but one would not expect a different result.
Related posts:
Full access? Get Clinical Tree
