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11 Psychopharmacology for the Pain Specialist

11 Psychopharmacology for the Pain Specialist
The Massachusetts General Hospital Handbook of Pain Management

11
Psychopharmacology for the Pain Specialist

Daniel M. Rockers and Scott M. Fishman

It was a most repugnant undertaking to have to treat a group of complaints which, as all authors are agreed, are typified by instability, irregularity, fantasy, unpredictability—complaints which are governed by no law or rule, and whose diverse manifestations are connected to no serious theoretical formulation.
—From “Traite Clinique et Therapeutique de l’Hysterie,” Paul Briquet

I. Antidepressants

1. Cyclic antidepressants

2. Monoamine oxidase inhibitors

3. Selective serotonin reuptake inhibitors

4. Atypical antidepressants
II. Antipsychotics

1. Typical neuroleptics

2. Atypical neuroleptics
III. Mood stabilizers
IV. Anxiolytics

1. Benzodiazepines

2. Buspirone
V. Psychostimulants
VI. Conclusion
Selected Reading

Knowledge of psychopharmacology is important for a pain practitioner because of the significant overlap of psychiatric diagnoses with chronic pain conditions, and because the common psychopharmacologic medication groups are used as analgesics. Many of these agents have multiple mechanisms of action, which accounts for their dual effects. In this chapter, psychotropic medications and their role in pain treatment are reviewed. Because of the high comorbidity of depression and pain, antidepressants—the largest category—are covered first. Next, medications that directly affect cognitive functioning—antipsychotics or neuroleptics—are reviewed. Mood stabilizers, used to treat bipolar disorder and derivative conditions, are next. Anxiolytics and psychostimulants conclude the section.
I. ANTIDEPRESSANTS
In the majority of cases, patients with chronic pain are prescribed an antidepressant or have already been taking one. Antidepressants often serve a dual role: treating a mood disorder as well as independently addressing pain symptoms.
The earliest forms of the currently used antidepressants were tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), each with inhibitory actions on norepinephrine (NE) and serotonin (5-HT) reuptake. These were the drugs of choice for treating depression until the 1980s, when the selective serotonin reuptake inhibitors (SSRIs) were found to possess substantial antidepressant efficacy. The SSRIs revolutionized the treatment of depression by offering efficacy with greatly reduced side-effect profiles.
Over the past decade, numerous atypical antidepressants have been developed, including norepinephrine and dopamine reuptake inhibitors (NDRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and serotonin-2 antagonist/reuptake inhibitors (SARIs). These newer agents are currently undergoing clinical trials to assess their relative efficacy when compared with that of standard TCAs and SSRIs. When first reported to be analgesic, TCAs were thought to work via relieving the depression component of pain. It is now well known that relieving depression by any method is likely to decrease pain. Not all antidepressants, however, have independent analgesic properties.
1. Cyclic antidepressants
Indications
TCAs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of major depressive disorders, and for the treatment of secondary depression in other disorders. In treating chronic pain, they are considered to have independent analgesic effects. A reasonable goal for using TCAs as analgesics is decreasing pain intensity from unbearable to bearable. Some mild side effects may be unavoidable in exchange for analgesia.
Mechanisms
All tricyclics inhibit both serotonergic and noradrenergic reuptake; and these effects are seen early, whereas clinical benefits often begin 2 to 3 weeks after initiation of treatment.
Misconceptions
Misconceptions about TCAs as analgesics are common. For instance, there is not a clear therapeutic window of dosages above and below which analgesia is diminished. Another misconception is that analgesia requires only low doses of TCA. Evidence suggests that analgesia is maximized with increased doses as well as with time. The time course of TCA analgesia varies between 1 and 120 days, suggesting that initial early analgesia is maximized over time. Duration of TCA analgesia also persists over time with maintenance of therapy. Thus, when clinicians choose to use TCAs as analgesics, they are encouraged to be patient with effects that may increase over weeks and to push the dosage upward, as long as side effects are tolerated, to increase efficacy.
Adverse reactions
The main side effects of cyclic antidepressant drugs include anticholinergic reactions (constipation and dry mouth) and cardiovascular effects. Other effects include orthostasis, sedation, extrapyramidal syndromes (tics, tremor, dyskinesia), weight gain, and sexual dysfunction. Prior to initiating treatment, routine laboratory screening may include a complete blood count, electrolytes (disturbances such as hypokalemia can precipitate cardiac arrhythmias), blood urea nitrogen, creatinine, and liver function tests. Some possible side effects of TCAs include jaundice, leukopenia, and rashes.
Other screening may include an electrocardiogram: although tricyclics are antiarrhythmic at therapeutic dosages, at supratherapeutic dosages they can be cardiotoxic. They can increase myocardial irritability, induce hypotension and tachycardia, decrease contractility, and increase conduction delays. Relative contraindications include second-degree heart block, structural heart disease, right bundle branch, and left bundle branch block. As patients with any of these disorders may develop bradyarrhythmia when prescribed tricyclics, they should be started on low doses that increase gradually, and they should be monitored by a cardiologist. Recent myocardial infarction is an absolute contraindication, as is closed angle glaucoma.
TCAs interact with multiple neurotransmitter systems and as a result present with a wider side-effect profile than SSRIs. Combining TCAs with opioids can lead to decreased intestinal motility, already a problem for many patients taking opioids. Additive anticholinergic and opioid effects on the bowels can lead to treatment resistant constipation or ileus.
Withdrawal may manifest as anxiety, fever, sweating, myalgia, headache, nausea, vomiting, dizziness, dyskinesia, or akathisia. Overdose with TCAs can be lethal. Toxicity results from anticholinergic effects and central nervous system (CNS) effects (including seizures and coma). The most hazardous side effect is cardiac toxicity, especially QRS complex widening. TCA overdose is a leading cause of drug-related overdose sequelae and death. Since three to five times the therapeutic dose of a TCA is potentially lethal, this low therapeutic index (ratio of toxic to therapeutic dose) should make prescribers vigilant. This is probably a large part of the reason SSRIs are often chosen over TCAs as first-line antidepressants.
Dosages and monitoring
As a general principle, dosing should start at the low end of the dose range and be titrated upward in 10- to 25-mg increments per week until a therapeutic level is reached (Table 1). As this minimizes side effects, patients are less likely to reject the therapy. Titration may need to be more rapid when TCAs are used for depression. Although somewhat controversial, it is generally agreed that plasma levels may be clinically valuable when using imipramine, desipramine, or nortriptyline to treat depression. Controversy on this issue stems from unclear correlation of plasma levels with clinical effects. Plasma levels of nortriptyline may be especially useful, because a therapeutic level may exist at a dose (e.g., 150 mg) above which the drug is actually less effective.

Table 1. Tricyclic antidepressants

The effects of all antidepressants are often delayed. They may be seen anywhere from 2 to 6 weeks after beginning a trial at therapeutic dosages. If the drug is found to be effective, the patient should continue the medication for 6 to 12 months to prevent relapse. The dosage should not be decreased during the maintenance phase of treatment. If a patient has had multiple recurrences of illness, an indefinite length of treatment may be indicated.
2. Monoamine oxidase inhibitors
Indications
MAOIs (Table 2) are approved for use in major depression, double depression (dysthymia superimposed on major depression), psychotic depression, social phobia, and simple phobias, and they are often also used to treat anxiety, panic disorder, and obsessive compulsive disorder. They are not considered first-line agents in the treatment of major depression because of their high incidence of side effects, dietary restrictions, and lethality in overdose. “Atypical” subtypes of depression involving mood reactivity, increased appetite, hypersomnia, leaden paralysis, and rejection sensitivity may respond better to MAOIs than to other agents.

Table 2. Monoamine oxidase inhibitors

Mechanisms
MAOIs work by binding to the enzyme monoamine oxidase, thus inhibiting the breakdown of monoamines at the synaptic junction. This results in increased concentration and availability of the neurotransmitters epinephrine, norepinephrine, and dopamine at various storage sites in the central and sympathetic nervous system.
MAOIs require up to 2 weeks to achieve maximal MAO inhibition, and clinical effects may not be seen for 2 to 4 weeks, although an energizing effect may occur within a few days following initiation of treatment. Table 2 offers some dosage guidelines for MAOIs. Unlike standard TCAs and SSRIs, MAOIs have a short half-life and require twice-daily dosing; this factor can be significant.
Adverse reactions
Patients taking MAOIs should avoid foods high in tyramine content, such as cheeses, yeast supplements, and aged alcohols, as they may precipitate a hypertensive crisis. Symptoms include occipital headache, neck stiffness or soreness, dilated pupils, tachycardia or bradycardia, and constricting chest pain. MAOIs should be used with caution in patients with cerebrovascular disease, cardiovascular disease, or hypertension.
Side effects include constipation, anorexia, nausea, vomiting, dry mouth, urinary retention, drowsiness, headache, dizziness, and weakness. As with SSRIs and TCAs, sexual dysfunction may occur, manifested as impotence, anorgasmia, decreased libido, ejaculation difficulties, and, rarely, priapism.
TCAs and SSRIs should be used very cautiously with MAOIs: fatalities have been reported in patients taking fluoxetine with MAOIs. Concomitant use of MAOIs and SSRIs or meperidine runs a risk for development of serotonin syndrome. Symptoms of serotonin syndrome include CNS irritability, myoclonus, diaphoresis, and elevated temperature. Severe cases may result in death. Patients should discontinue MAOIs for at least 2 weeks before beginning an SSRI.
Dosages and monitoring
It appears that optimal antidepressant efficacy occurs when MAOIs are given at doses that reduce MAO activity by at least 80% (see Table 2). Liver function tests should be monitored periodically, as MAOIs are associated with hepatotoxicity. With long-term use, MAOIs may impair their own metabolism. Unfortunately, MAOI serum levels are not useful for guiding therapy.
3. Selective serotonin reuptake inhibitors
Indications
Since the introduction of fluoxetine (Prozac) in 1987, several other SSRIs have been introduced and have revolutionized firstline therapy for depression (Table 3). Although SSRIs were initially introduced for use in major depressive disorder, the FDA has approved the use of these agents for other indications, including panic disorder, bulimia nervosa, and obsessive-compulsive disorder. In addition, SSRIs are often used by clinicians for a variety of other conditions, including premenstrual syndrome, chronic fatigue syndrome, intermittent explosive disorder, and chronic pain management.

Table 3. Selective serotonin reuptake inhibitors

Mechanisms
SSRIs act via specific mechanisms in the CNS and may have fewer side effects than other antidepressants as a result. The immediate effect of the SSRIs on the CNS is blockade of the presynaptic serotonin reuptake pump. Although there are reports of SSRI-induced analgesia, to date these are largely anecdotal. The only controlled trial [by Max (1992)] did not find these agents to possess independent analgesia.
Adverse reactions
SSRIs have fewer side effects than many other antidepressants because they have minimal effects on neurotransmitters other than serotonin, although they may cause some undesirable symptoms. Possible CNS effects include headaches, stimulation or sedation, fine tremor, tinnitus, and rare extrapyramidal symptoms including dystonia, akathisia, dyskinesia, and possibly tardive dyskinesia. Cardiovascular effects are rare, but there are reports of tachycardia, bradycardia, palpitations, and vasoconstriction. Gastrointestinal effects include nausea, vomiting, anorexia, bloating, and diarrhea. The limited sedation associated with these agents makes them ideal additions for patients who are on sedating analgesics and experiencing pain. Other serotonergic drugs should be avoided or used with caution because of the possibility that serotonergic syndrome may develop. Approximately 10% to 15 % of patients taking an SSRI experience sexual side effects of decreased libido, impotence, ejaculatory disturbances, and anorgasmia.
Dosages and monitoring
No initial laboratory workup is required. Dosage titration is usually based on clinical response and side effects. Beneficial effects are usually not seen prior to 2 to 3 weeks. Dosages must be tapered slowly to avoid withdrawal symptoms.
4. Atypical antidepressants
Other classes of antidepressants have been developed to target specific neurotransmitter interactions at the synaptic level. They maximize therapeutic benefits while minimizing side effects. Included are norepinephrine and NDRIs such as bupropion (Wellbutrin), SNRIs such as venlafaxine (Effexor), and SARIs represented by trazodone (Desyrel).
Bupropion, an NDRI, is metabolized to hydroxybupropion, a powerful inhibitor of both noradrenergic and dopaminergic pumps. This agent differs from most other antidepressants in that it has psychostimulant properties. There have been no controlled clinical trials of its efficacy in the treatment of chronic pain; however, its stimulating properties offer advantages in treating depression in patients on sedating drugs such as opioids.
Treatment should be initiated at 75 to 100 mg once per day, starting in the morning to avoid potential insomnia. It can then be given twice daily and the dose can be gradually increased, although never above 450 mg/day or 150 mg in a single dose. A new sustained-release form is available, saving the practitioner from concern about dosage splitting. Seizures occur in approximately 0.4% of patients at dosages less than 450 mg/day, and in 4% of patients when dosages range from 450 to 600 mg/day. Therefore, dosages above 450 mg/day should be avoided. Bupropion should also be avoided in patients with seizure disorder or those taking medications that may cause seizures. The most common adverse effects are headache, insomnia, upper respiratory complaints, nausea, restlessness, agitation, and irritability. In overdose, dosages as high as 4,200 mg have been taken without death.
Venlafaxine is an SNRI with some anecdotal evidence of efficacy in the treatment of chronic pain. Potential analgesia is suggested by its profile of dual inhibition of serotonin and norepinephrine reuptake, which is similar to that of proven analgesic antidepressants such as imipramine, amitriptyline, and desipramine. Venlafaxine differs from these agents in its lack of anticholinergic, antiadrenergic, and antihistaminergic side effects, a difference that has unknown bearing on analgesia.
Although venlafaxine is available in extended-release form, it is traditionally given in two or three divided daily doses beginning at 75 mg/day and increased to as high as 375 mg/day. No laboratory studies are indicated and serum levels of venlafaxine are clinically useful. Side effects include nausea, headache, somnolence, dry mouth, dizziness, nervousness, constipation, anxiety, anorexia, blurred vision, and sexual dysfunction. No reports of fatal overdose have been reported. Venlafaxine should not be used in conjunction with MAOIs, and it may affect the hepatic metabolism of other medications.
Trazodone and nefazodone are SARIs by virtue of blocking serotonin-2 receptors as well as serotonin reuptake. These agents are used for depression and insomnia. Their usefulness in the treatment of chronic pain is undetermined, but given the incidence of insomnia in pain patients, they are likely to have at least a potential adjuvant role. Trazodone is less effective for the treatment of depression than nefazodone, although trazodone may be more sedating.
Dosages should begin as low as 50 mg/day but can be increased to as high as 600 mg/day in twice-daily divided doses. No laboratory studies are indicated before beginning SARIs, and plasma levels are not clinically useful. Side effects include sedation, orthostatic hypotension, dizziness, headache, nausea, dry mouth, and gastrointestinal (GI) upset. There are no anticholinergic effects of SARIs. Rare cases of cardiac arrhythmias have been reported. An infrequent but serious side effect is priapism (1/1,000 to 1/10,000), and patients should be warned of this prior to starting treatment. There have been no reported cases of death following overdose with SARIs taken alone.
SARIs should not be used in conjunction with MAOIs. Also, use with astemizole or terfenadine may decrease hepatic P450 metabolism of these compounds, resulting in cardiac arrhythmias. Finally, SARIs may increase serum levels of triazolam (Halcion) and alprazolam (Xanax).
II. ANTIPSYCHOTICS
Indications
Antipsychotics are used to treat various psychoses and schizophrenia, as well as psychotic symptoms such as paranoid disorders, schizophreniform disorder, brief psychoses, and psychoses associated with mood disorders. They have been used to treat pain as well as personality disturbances, although the potentially permanent side effect of tardive dyskinesia makes chronic usage inadvisable.
Antipsychotics are also known as neuroleptics because of the often-irreversible side effects they produce. Because neuroleptic agents poses some degree of independent analgesia, they can have a role in chronic pain when used for very short periods of time. Their potential efficacy may be further realized with the advent of new antipsychotic agents that may have greatly reduced side effect profiles. Should the risk of tardive dyskinesia be eliminated, chronic usage of these agents would be markedly safer and thus the analgesia they offer may be more attractive as an adjunct in the treatment of chronic pain.
1. Typical neuroleptics
Mechanisms
Typical neuroleptics (Table 4) function as antipsychotics as a result of their dopaminergic antagonism, particularly at postsynaptic D2 receptors, probably in pathways from the midbrain to the limbic system and the temporal and frontal lobes. Typical neuroleptics also may affect cholinergic, alpha-1-adrenergic, and histaminic systems. These actions are responsible for many of the significant side effects of typical neuroleptics.

Table 4. Typical neuroleptics

Adverse reactions
Antipsychotics carry a risk of extrapyramidal symptoms including acute dystonia, akathisia, pseudoparkinsonism, and tardive dyskinesia; those with the least anticholinergic effects have the greatest risk. Neuroleptics also have effects on numerous hormonal systems. Prolactin may be elevated by neuroleptics, with possible effects that include amenorrhea, galactorrhea, and false-positive pregnancy tests in women and gynecomastia and galactorrhea in men. Neuroleptics may cause hypothalamic dysfunction (leading to the syndrome of inappropriate antidiuretic hormone and to temperature regulation difficulties) or disrupt serum glucose levels. Neuroleptic malignant syndrome is a particularly serious, albeit rare, event.
Anticholinergic activity may cause dry membranes, blurred vision, constipation, urinary retention, and confusion or delirium. Histaminic effects include sedation, cognitive impairment, and weight gain. A combination of dopaminergic, anticholinergic, and alpha-1-adrenergic effects may cause sexual dysfunction. In addition, neuroleptics may lower the seizure threshold, seen most in lower-potency agents such as chlorpromazine (Thorazine) and least in high-potency agents such as haloperidol. Cardiovascular effects include hypotension, tachycardia, dizziness, fainting, nonspecific electrocardiographic changes, and rarely arrhythmias, including torsades de pointes, and sudden cardiac death.
2. ATYPICAL NEUROLEPTICS
Dosages and monitoring
No routine laboratory tests are necessary for the prescribing of antipsychotic agents. The physician should be aware of the emergence of extrapyramidal side effects and should warn patients about potential tardive dyskinesia.
Mechanisms
The atypical neuroleptics include agents such as risperidone (Risperdal), clozapine (Clozaril), and olanzapine (Zyprexa) (Table 5). These agents have D2 antagonism but to a lesser degree than typical neuroleptics. Additionally, they appear to block serotonin-2 receptors and, to variable degrees, the D4 receptor. Atypical neuroleptics may be more efficacious than typical neuroleptics, particularly with negative psychotic symptoms. However, no controlled studies of the use of atypical neuroleptics in the treatment of chronic pain have been conducted. One advantage of atypical neuroleptics over typical neuroleptics is the lower incidence of extrapyramidal side effects.

Table 5. Atypical neuroleptics

Adverse effects
Clozapine is considered a second-line treatment because of the possibility of fatal agranulocytosis in about 1% of patients. Olanzapine is similar in structure and mechanism to clozapine. Olanzapine has a low drug interaction potential and reduced incidence of extrapyramidal side effects. No incidents of leukopenia have been reported for olanzapine. Risperidone also has reduced incidence of extrapyramidal side effects and, like olanzapine, is not associated with agranulocytosis. Olanzapine appears to be more sedating than risperidone; risperidone can cause insomnia.
III. MOOD STABILIZERS
Indications
Mood stabilizers are used to treat bipolar disorder, which involves alternating periods and degrees of mania and depression. Lithium is the classic agent for treating bipolar disorder, but recently many other agents such as anticonvulsants (valproic acid, carbamazepine, gabapentin, and clonazepam) have gained popularity. The overlap of this group of drugs with those used to treat neuropathic pain is striking, and the meaning of this has not yet been clarified.
Whereas bipolar disorder is not overly common in the patient with chronic pain, it does occur and can be worsened by drugs that are commonly in the arsenal for pain. Analgesic agents that may provoke mania include antidepressants as well as steroids. However, several agents that are specifically effective against neuropathic pain also are helpful in treating bipolar disorder (i.e., carbamazepine and gabapentin) and are thus clear choices for treatment of comorbid bipolar disorder and chronic pain.
Lithium
Lithium has been used extensively for treatment of migraine and cluster headaches. However, there is no evidence of efficacy in the treatment of any other type of chronic pain. Lithium remains the most commonly used agent for treating bipolar disorder. A narrow therapeutic index and its frequent side effects limit its use.
Anticonvulsants
At present, it appears that all commonly used neuropathic analgesics are anticonvulsants, in that these agents are either directly used as antiseizure agents or otherwise as antiarrhythmics or local anesthetics. Anticonvulsant drugs, including carbamazepine (Tegretol), valproate (Depakote), phenytoin (Dilantin), gabapentin (Neurontin), and clonazepam (Klonopin) are widely used for treating chronic pain, neuropathic pain in particular. This same group of drugs is being used more and more widely in treating psychiatric disorders.
Mechanisms
The mechanisms of action of this diverse group are certainly varied, but all are thought to act as membrane stabilizers. Phenytoin and carbamazepine slow the rate of recovery of voltage-activated sodium ion channels from inactivity. Valproic acid is believed to increase gamma-aminobutyric acid (GABA) concentrations in the brain, clonazepam stimulates GABAergic pathways, and the action of gabapentin is unknown (although it functions as a GABA analog, it does not act as GABA receptors). The mechanism of lithium’s therapeutic effects is unknown, but it is postulated to be either endocrine, neurotransmissive, circadian, or cellular. Lithium is not a sedative, depressant, or euphoriant. Possible side effects include blood dyscrasias (although less common than with carbamazepine) and hepatitis.
IV. ANXIOLYTICS
Anxiety disorders may occur in a large percentage of patients with chronic pain. These disorders include panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. These often present with somatic symptoms including chest pain, GI upset, and neurologic symptoms (headache, dizziness, syncope, and paresthesias). Treatment of chronic pain that is comorbid with an anxiety disorder should include anxiolysis as part of the analgesic strategy.
1. Benzodiazepines
Benzodiazepines are the most popular medication for anxiety and in fact are the most widely prescribed medication of any type. Clonazepam is considered both a psychotropic agent (anxiolytic) and a neurologic agent (anticonvulsant). This suggests its possible usefulness in the pain clinic pharmacologic armamentarium.
Indications
Benzodiazepines are approved for use with anxiety disorders, alcohol withdrawal seizures, and insomnia. They have also been used to treat akathisia, agitation (including mania), depression, catatonia, and muscle spasm.
Mechanisms
Benzodiazepines depress the CNS at the levels of the limbic system, brainstem reticular activating formation, and cortex by binding to and facilitating the action of GABA. Although they are not primary analgesics, benzodiazepines often have a role in the analgesic regimen.
Adverse reactions
The most common side effect of benzodiazepines is sedation and respiratory depression. Rapid withdrawal from benzodiazepines can result in rebound insomnia, anxiety, delirium, or other withdrawal symptoms. Severe withdrawal reactions include seizures, psychosis, and death. Discontinue dosages by gradually tapering.
Dosages and monitoring
As with any medication in which tolerance develops, dosage ranges tend to be open-ended. In overdose, benzodiazepines are rarely fatal if taken alone, although they may cause respiratory depression. If taken with alcohol or barbiturates, however, benzodiazepines can be fatal, with symptoms including hypotension, depressed respiration, and coma. The choice of a specific benzodiazepine is often based on onset of action and half-life (Table 6). In general, short-acting agents are used to treat insomnia and acute anxiety, whereas long-acting agents are used to treat chronic conditions.

Table 6. Benzodiazepines: onset and half life

2. Buspirone (buSpar)
Although not known to be efficacious for the treatment of pain, buspirone can be an effective anxiolytic. Buspirone acts as a 5-HT- 1A agonist. Buspirone may potentiate the antidepressant and antiobsessional effects of SSRIs. It is also being studied for use in post-traumatic stress disorder.
No laboratory studies are required before initiating treatment with buspirone. Patients may take 5 to 30 mg/day in divided doses, starting at 5 mg three times a day and increasing to as high as 10 mg three times a day. Anxiolytic effects require 1 to 4 weeks to appear. Buspirone has relatively few side effects; less than 10% of patients experience headache, dizziness, lightheadedness, fatigue, paresthesias, and GI upset. Buspirone has a low potential for abuse or addiction and it does not impair psychomotor or cognitive functions. There have been no reports of withdrawal symptoms or death from overdose. However, buspirone should be used with caution in patients taking MAOIs, as this combination may result in elevated blood pressure. Also, buspirone inhibits the metabolism of benzodiazepines and haloperidol.
V. PSYCHOSTIMULANTS
Indications
Although approved indications for psychostimulants include attention deficit disorder, Parkinson’s disease, and narcolepsy, they are also used for treatment-resistant depression, to augment antidepressants, and in the treatment of sedation or fatigue in terminal illness. They are the only immediate-acting “antidepressants.” Although they have been used as so-called diet pills, they can improve appetite in cancer treatment. Additionally, psychostimulants are used to counter iatrogenic sedation, most commonly caused by opioid analgesics. Common psychostimulants include dextroamphetamine, methylphenidate, and magnesium pemoline.
Mechanisms
At normal dosages, amphetamines stimulate the release of norepinephrine. As the dosage increases, they cause the release of dopamine, which accounts for the behavioral changes and the reinforcing properties. At excessive dosages, amphetamines cause the release of serotonin, which may be associated with the amphetamine psychosis. Methylphenidate blocks the reuptake of dopamine. Magnesium pemoline exhibits effects similar to those of amphetamines and methylphenidate. The stimulant effects appear to be mediated through dopaminergic mechanisms, but weak sympathomimetic effects are also involved. Tachyphylaxis associated with psychostimulants results from their being indirect agonists. Thus, by stimulating the release of endogenous neurotransmitters, they deplete the stores of these mediators.
Adverse reactions
Risk factors include hypertension and tachyarrhythmias, and tension. Liver disease is a contraindication (pemoline is not used as a first-line treatment because of reports of late-onset hepatotoxicity), as are functional psychosis, anxiety, and anorexia. A 20% to 50% incidence of tics occurs in patients with Tourette’s syndrome. Other adverse effects commonly seen include anorexia, irritation, sadness, and clingy behavior.
Dosages and monitoring
Psychostimulants should be used cautiously in patients with existing drug or alcohol abuse problems. Start at a low dosage and then increase gradually over several days (Table 7). Because of its short half-life, methylphenidate must be dosed twice daily (it is also available in extended release form). Patients should not stop taking the drug abruptly.

Table 7. Psychostimulants: dosage and cautions

VI. CONCLUSION
Treating pain often requires the use of medications that impact both nociceptive and non-nociceptive processes. Without adequate familiarity with psychopharmacologic agents, the pain specialist risks having a limited analgesic repertoire and may overlook potentially beneficial possibilities as well as potential adverse complications of polypharmacy. The ongoing revolution in development of psychoactive drugs will surely impact pain management, and drugs will very likely gain increased prominence in the arsenal against pain.
SELECTED READING

1.
Bezchlibnyk-Butler KZ, Jeffries JJ, Martin BA, eds. Clinical handbook of psychotropic drugs, 4th ed. Seattle: Hogrefe Huber, 1994.

2.
Bloom FE, Kupfer DJ, eds. Psychopharmacology: The fourth generation of progress. New York: Raven Press, 1995.

3.
Ciraulo DA, Shader RI, Greenblatt DJ, Creelman W, eds. Drug interactions in psychiatry, 2nd ed. Baltimore: Williams & Wilkins, 1995.

4.
Guze B, Richeimer S, Szuba M, eds. The psychiatric drug handbook. St. Louis: Mosby–Year Book, 1995.

5.
Hyman SE, Arana GW, Rosenbaum JF, eds. Handbook of psychiatric drug therapy, 3rd ed. Boston: Little, Brown, 1995.

6.
Kaplan HI, Sadock BJ, eds. Comprehensive textbook of psychiatry, 6th ed. Philadelphia: Williams & Wilkins, 1995.

7.
Magni G. The use of antidepressants in the treatment of chronic pain: A review of the current evidence. Drugs 1991;42:730–748.

8.
Sindrup SH, Brosen K, Gram LF. Antidepressants in pain treatment: Antidepressant or analgesic effect? Clin Neuropharmacol 1992;15(suppl 1):636A–637A.

9.
Stahl SM. Essential psychopharmacology: Neuroscientific basis and clinical applications. Boston: Cambridge University Press, 1996.

10.
Zitman FG, Linssen AC, Edelbroek PM, Van Kempen GM. Clinical effectiveness of antidepressants and antipsychotics in chronic benign pain. Clin Neuropharmacol 1992;15(suppl 1):377A–378A.

11.
Max MB, Lynch SA, Muir J, Shouf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992;326:1250–1256.

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