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In the Name of GOD Psychopharmacology for Pain Medicine A large percentage of patients with chronic pain disorders have coexisting, or comorbid, psychiatric conditions, which are the most prevalent comorbidities in patients with chronic pain. This is particularly true in patients with chronic low back pain. Patients with pain and psychiatric comorbidity are commonly referred to pain medicine clinics and frequently present on 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. Psychotherapeutic modalities, such as cognitive behavioral therapy, relaxation training, or biofeedback, play an important role in the treatment of both psychiatric and chronic painful illness, and in some cases are the preferred method of treatment. As with many of the medications used in pain medicine, psychoactive medications with reported analgesic properties do not always have a Food and Drug Administration (FDA) indication for this purpose, but can legally be prescribed for off-label use. EPIDEMIOLOGY Over two decades of studies of U.S. pain clinic populations have shown that 60% to 80% of these patients have psychiatric illnesses by DSM criteria. Estimates are lower in persons with pain in primary care, institutional, and community settings, but regardless of setting, given the prevalence of persistent pain in adults, estimated at 20% to 45%, pain-psychiatric comorbidity constitutes an important public health problem. Patients with psychiatric illness report greater pain intensity, more painrelated 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. Major depression alone affects 30% to 50% of all pain clinic patients, followed by anxiety disorders, personality disorders, somatoform disorders, and substance use disorders. MAJOR DEPRESSION AND SUBTHRESHOLD DEPRESSION According to the DSM-IV, major depressive disorder (MDD) requires two key features: 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. 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, and if not treated effectively, it will reduce the effectiveness of all pain treatments. 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 for 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 them for 6 to 12 months for the treatment of an initial depressive episode, and 5 years for the treatment of a recurrent depressive episode. 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. Often, patients with chronic pain are on multiple medications that can potentiate the side effects of antidepressants, such as headache, nausea, constipation, or sedation, so “starting low and going slow” is even more important in this population. Typically, in the initial treating period, re-evaluations are done every 2 to 4 weeks, with dose adjustments if indicated. Monoamine oxidase inhibitors (MAOIs), such as phenelzine, which are rarely prescribed anymore, should not be prescribed with other antidepressants concurrently. Because of the inherent risks of these medications, they should be used only by experienced psychopharmacologists. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS) Since the introduction of fluoxetine (Prozac) in 1987, many 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. While a few case reports have shown improvements in diabetic neuropathic pain on SSRIs, double-blind, placebo-controlled clinical trials that exclude patients with depression have not consistently demonstrated analgesic benefit. Patients should begin on one-half of the usual dose for a week and then to the standard dose, 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 due to possible comorbid pain and depression. Rare side effects include dystonia, akathisia, palpitations, a lowered seizure threshold, serotonin syndrome, or syndrome of inappropriate antidiuretic hormone (SIADH). Selective Serotonin Reuptake Inhibitors (SSRIs) 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 TRICYCLIC ANTIDEPRESSANTS (TCAs) 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 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 the patient with chronic pain, particularly if cost is a factor. All TCAs are equally effective for the treatment of depression, and the choice of a particular one is determined by side effects. 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. Prior to initiating treatment patients should have laboratory screening of electrolytes, BUN, creatinine, and LFTs. TCAs also have quinidine-like properties, are potentially proarrhythmic, and can prolong the QTC interval. All patients aged over 40 years or with any history of cardiac disease should have a baseline EKG, with particular attention to the QTC interval, checking that it is less than 450 ms. TCAs are strongly protein-bound (85% to 95%) and undergo first-pass hepatic metabolism. Subsequent stages involve demethylation, oxidation, and glucuronide conjugation. 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 75–150 mg). 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. 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. Many patients are referred to the 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. Tricyclic Antidepressants (TCAs) 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 SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs) The nontricyclic SNRIs are a newer group of antidepressants that, like the TCAs, act by inhibiting serotonin and norepinephrine 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, duloxetine, and, most recently, milnacipran are the main drugs in this category and have significantly less alpha-1, cholinergic, or histamine inhibition. In the United States, milnacipran (Savella®) is FDA approved for the treatment of fibromyalgia but not depression, and thus will not be discussed in detail. Duloxetine (Cymbalta) is an SNRI approved for use in the United States for diabetic peripheral neuropathic pain, 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, and thus it is the treatment of choice for patients with neuropathic pain and psychiatric comorbidity. OTHER ANTIDEPRESSANTS Bupropion is a noradrenergic and dopaminergic reuptake pump inhibitor, prolonging the time norepinephrine 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, ADHD, and smoking cessation, at doses up to 600 mg/day. Two studies have shown that bupropion has independent analgesic effects in a variety of neuropathic conditions. Treatment should start at 75 to 100 mg in the morning to avoid insomnia that 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. Mirtazapine is an antidepressant with antagonism of serotonin and central presynaptic alpha2-adrenergic receptors, stimulating serotonin and norepinephrine release. This serves to potentiate serotonergic and noradrenergic transmission, while having no anticholinergic effects. Trazodone is a serotonin-2 antagonist/reuptake inhibitor (SARI), and is used for major depression and insomnia. The sedative qualities of trazodone are so great that few patients are able to get to high enough of a dose to be in the effective antidepressant range. Miscellaneous Antidepressants 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 Mirtazapine (Remeron) 15 mg qhs 30–45 mg qd 60 mg qd Nefazodone (Serzone) 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 ANXIETY DISORDERS Anxiety disorders are a broad spectrum of disorders, including generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and PTSD. There is a high prevalence rate of anxiety disorders in chronic pain clinic populations, with 30% to 60% of patients having anxiety at pathological levels. Generalized anxiety disorder is the most frequent anxiety disorder affecting pain patients. Patients’ situational anxiety is often anxiety about pain and its negative consequences. Patients may be conditioned to be excessively fearful that activities will cause uncontrollable pain, causing avoidance of those activities, which in some patients can be extreme, almost phobic. Also, pain may activate thoughts that patients are seriously ill. Pain-specific anxiety as well as generalized anxiety amplify pain perception and pain complaints through several biopsychosocial mechanisms, including sympathetic arousal with noradrenergically mediated lowering of nociceptive threshold, increased firing of ectopically active pain neurons, excessive cognitive focus on pain symptoms, and poor coping skills. TREATMENT Antidepressants are effective, but generally at higher doses than what is typically prescribed for depression. Anxiolytics, such as benzodiazepines and buspirone, are most useful in the initial treatment stages to stabilize a disorder. ANTIDEPRESSANTS BENZODIAZEPINES (BZDs) BUSPIRONE These medications are useful in the treatment of acute anxiety, panic attacks, and the stabilization of generalized anxiety. Occasionally, anxiety cannot be stabilized with antidepressants and patients remain on BZDs in the long term. BZDs bind to the BZD component of the gammaaminobutyric acid (GABA) receptor, an inhibitory neurotransmitter. They depress the CNS at the levels of the limbic system, brainstem reticular formation, and cortex. Acute anxiety or panic attacks can be treated with short-acting BZDs, such as lorazepam 0.5 to 2 mg q6hr, prn, which has a rapid onset of action (10 to 15 min) and a half-life of 10 to 20 hr. Caution should be taken in prescribing short half-life drugs, such as alprazolam. While it has a rapid onset of action, it typically lasts only 2 to 3 hr and many patients have significant rebound anxiety. Buspirone is also an effective anxiolytic. It acts as a serotonin agonist. It is especially useful in treating patients with a history of substance abuse who may abuse BZDs. It has no addictive properties, and does not impair psychomotor or cognitive functions. It is started at 5 mg tid and can be advanced as high as 10 mg tid. Unlike the short-acting BZDs that deliver anxiolysis with the first dose, buspirone requires 1 to 4 weeks of administration for antianxiety benefits to appear. Patients can experience headache, dizziness, paresthesias, and GI upset. Clonazepam 0.25 to 1 mg tid, a long-acting BZD, is often used in conjunction with a short-acting agent or an antidepressant to stabilize persistent anxiety or prevent acute anxiety attacks. Diazepam, which also has psychoactive metabolites lasting several days, and flurazepam, are other agents with long halflives. Benzodiazepines (BZDs) Drug Onset Half-Life (hr) Alprazolam (Xanax) Intermediate 6–20 Chlordiazepoxide (Librium) Intermediate 30–100 Clonazepam (Klonopin) Intermediate 18–50 Clorazepate (Tranxene) Rapid 30–100 Diazepam (Valium) Rapid 30–100 Estazolam (ProSom) Intermediate 10–24 Flurazepam (Dalmane) Rapid-intermediate 50–160 Lorazepam (Ativan) Intermediate 10–20 Midazolam (Versed) Rapid 2–3 MOOD STABILIZERS AND ANTIEPILEPTICS Mood stabilizers are agents that possess both antimanic and antidepressant properties. Some of these medications are antiepileptic drugs. This class of medications is often used to treat patients with chronic neuropathic pain, trigeminal neuralgia, and headache. Some of the medications in this class are lithium, valproic acid (Depakote is the longer-acting brand name formulation), carbamazepine (Tegretol®), and lamotrigine (Lamictal®). The anticonvulsants are frequently prescribed in pain medicine and are documented analgesics for a variety of conditions, most often neuropathic pain and headache prophylaxis. LITHIUM Lithium is the most commonly prescribed mood stabilizer for bipolar disorder. It is also used as an augmentation agent for MDD, administered in conjunction with antidepressants. lithium has been used as prophylaxis for chronic daily headaches and cluster headaches. VALPROIC ACID Depakote is the brand name of long-acting valproic acid, with a duration of action of 8 to 12 hr. It has both antimanic and antidepressant effects, although with less anti depressant effect than lithium. It is also useful as an augmentation agent in depression. Depakote can also be used for the treatment of impulsivity and aggression. Valproic acid has an established use in migraine prophylaxis, and neurologists have extensive experience with it in seizure treatment. This medication should not be given to pregnant women, as it is associated with neural tube defects. LAMICTAL Lamotrigine, or Lamictal, as it is known by its trade name, is an antiepileptic medication very commonly prescribed for seizure control by neurologists and for mood stabilization by psychiatrists. It is often prescribed for bipolar patients with prominent depressive symptomatology and it appears to be more effective in preventing depression than mania. Its mechanism for treating bipolar disorder is not known. Lamictal has been reported to reduce neuropathic pain in case reports. Lamotrigine does have an established use as a preventive agent in headache management, and a recent systematic review concludes that it is efficacious in reducing the frequency of migraines. Although generally well tolerated, rash may occur in up to 10% of individuals and Steven-Johnson syndrome. This medication is often started 25 mg daily for 2 weeks, then 50 mg daily for 2 weeks, 100 mg daily for 1 week, and then 200 mg daily for most patients. CARBAMAZEPINE Carbamazepine, also know as Tegretol, is an anticonvulsant used to treat partial seizures and generalized seizures. Carbamazepine is a well-established mood stabilizer and is also the first-line treatment for trigeminal neuralgia and other neuropathic pain disorders with a lancinating quality. This medication is usually started at doses between 200 and 400 mg daily in divided doses with a therapeutic dose range of 750 to 2500 mg daily in divided doses. NEUROLEPTICS Also termed “antipsychotics,” neuroleptics have been available for almost 50 years. They are used to treat any psychotic process, the hallmark illness being schizophrenia, and psychotic symptoms in depression, mania, or delirium are also indications for their use. Both the typical and newergeneration atypical neuroleptics have independent analgesic properties, and are effective analgesics for nociceptive and neuropathic conditions. However, based on a recent review of the literature, there is evidence that demonstrates a role for antipsychotics in treating many different types of pain including cancer pain and chronic non cancer pain, such as fibromyalgia, chronic headache, low back pain, musculoskeletal pain, chronic pain in older patients, chronic facial pain, and diabetic neuropathy. TYPICAL NEUROLEPTICS Typical neuroleptics act as antipsychotics through their antagonism of dopamine receptors, particularly the D2 receptors. They also have actions on histaminic, cholinergic, and alpha-1 adrenergic receptors. Selected Typical Neuroleptics Drug Usual Dose Maximum Dose Fluphenazine (Prolixin) 5–10 mg bid-tid 40 mg/day Haloperidol (Haldol) 2–5 mg bid-tid 100 mg/day Perphenazine (Trilafon) 8–16 mg bid-tid 64 mg/day Thiothixene (Navane) 5–10 mg tid 60 mg/day Trifluoperazine (Stelazine) 5–10 mg bid 40 mg/day Loxapine (Loxitane) 20–50 mg bid-tid 250 mg/day Chlorpromazine (Thorazine) 10–50 mg bid-qid 2000 mg/day Thioridazine (Mellaril) 100–200 mg bid-qid 800 mg/day ATYPICAL NEUROLEPTICS The atypicals have a lesser degree of dopamine D2 receptor antagonism and a greater degree of D4 receptor antagonism than the typical neuroleptics. Additionally, they have some degree of serotonin-2 receptor blocking. This mixed receptor profile results in far fewer extrapyramidal, anticholinergic, and cardiac side effects. The use of atypical neuroleptics in pain medicine will continue to grow. Case reports and retrospective studies indicate that they may be effective as a secondary or tertiary agents for migraine and chronic daily headache prophylaxis. They have been effective as abortive agents for cluster headache. Atypical Neuroleptics Drug Usual Dose Maximum Dose (Aripiprazole) Abilify 5 mg qd 30 mg qd (Clozaril) Clozapine 100–300 mg qd-bid 900 mg/day (Zyprexa) Olanzapine 5–15 mg qd 20 mg/day (Seroquel) Quetiapine 50–150 mg bid-tid 800 mg/day (Risperdal) Risperidone 2–4 mg qd-bid 16 mg/day (Geodon) Ziprasidone 20–40 mg bid 160 mg/day Thank you for your attention