Chapter 63. Psychopharmacology for the Pain Specialist

A pain patient from our center recently left a series of phone messages detailing his newly discovered powers of “dolphin-sonar,” and added that Elliott Ness had possession of his car. He was wondering if he could be provided with a skateboard with which to get around town. His verbal style was characterized by a bombastic manner and loose associations. Although previous conversations focused almost exclusively on his painful lower back, in these messages there was no mention of it.

This brief case sketch illustrates two important points regarding the difficulties the practitioner has in dealing with chronic pain. The first point is the high comorbidity of psychiatric diagnoses with chronic pain diagnoses. Of course, only few chronic pain patients have concomitant delusions as this patient did, but nearly all have had their lives disrupted to such an extent that a psychiatric diagnosis is highly possible. The second point has to do with the chronology of these conditions. It is often difficult to determine whether the pain caused the psychiatric diagnosis, the psychiatric condition caused the pain, or they happen to occur somewhat simultaneously. All of this suggests that a knowledge of psychopharmacology is important for a pain practitioner not only because there is a large overlap of psychiatric diagnoses with chronic pain conditions, but all of the common psychopharmacologic medication groups are also used as analgesics. Many of these agents have multiple mechanisms of action that account for their dual effects. However, the dramatic overlap of the analgesic and psychopharmacology drug arsenal suggests a significant degree of clinical homology in patients with chronic pain. Comprehensive pain management requires an understanding of basic principles of psychopharmacology. From the perspective of a non-mental health professional, it might seem fitting to ask, “Why psychopharmacology for the pain specialist?” There are several real answers to this important question:

• The majority of patients in chronic pain have comorbid psychiatric conditions, ranging from mild (anxiety, adjustment, depression) to severe (delusional, psychotic).
• Depression and anxiety are known to enhance perception of pain and may be a predominating component of some pain syndromes.
• Some psychiatric conditions manifest as pain or pain-like symptoms. For example, it has been suggested that complex regional pain syndrome (CRPS) is a conversion-like disorder.1
• Many psychiatric conditions are caused by, or are accompanied by, neurochemical abnormalities. These abnormalities may significantly affect the pain medications prescribed and may affect the pain condition in a significant manner. For example, serotonin is considered an important factor in pain states, as well as mood states.
• There may be malpractice suits brought against pain practitioners who do not adequately recognize or treat accompanying psychiatric conditions that affect pain states.
• Patients may often choose not to seek mental health treatment, even when instructed by the pain practitioner to do so. This may have to do with a patient’s financial state, insurance coverage, or the stigma associated with seeking help for emotional difficulties.

In the following pages, several psychotropic medications and their role in pain treatment are reviewed. Antidepressants are the largest category, and this is not surprising considering the high comorbidity of depression and pain. Anxiolytics are also reviewed, as anxiety is also commonly seen in many patients suffering from chronic pain. Also, neuroleptics—medications that affect cognitive functioning, affect movement, and treat delirium—are also reviewed here.

Improving Compliance

Even the best medication may be useless if the patient does not take it as prescribed. This is a matter of special concern when utilizing psychotropic medications because some patients may get the wrong message when being prescribed psychotropic agents. Patient education about any impending treatment will help balance patient expectations and have an impact on how patients respond to and tolerate any adverse effects that may arise. For example, this is especially important with depression, a condition in which motivation and ability to focus are quite low. Many patients do not recognize that some medications require several weeks to demonstrate results. Some patients incorrectly believe that all of their medication can be taken on an as-needed basis for symptom relief. Others may not understand the difficulties associated with abrupt discontinuance. Giving the patient information about their medications offers them a sense of some control, and obviously may go a long way toward better compliance.

Ease of use of a treatment will significantly impact compliance and the simplest effective drug regimen will help ensure that the treatment will be used. Many patients are taking a long list of medications, and minimizing polypharmacy may help with compliance with essential drug regimens. Consider nonbiological treatments when they are as effective as pharmacotherapy. Minimize risk of drug–drug interactions. Establish an ongoing therapeutic relationship. By all means, get to know your patient as a person, and not just as an illness or condition.

Description

Depression is one of the largest psychological issues comorbid with chronic pain. For example, major depression is found in 8% to 50% of patients with chronic pain, and dysthymia may be seen in greater than 75% of patients with chronic pain. In most cases of chronic pain, a patient will be prescribed an antidepressant or will already be taking one. Antidepressants often serve a dual role: treating a mood disorder as well as independently addressing pain symptoms. For these reasons, an awareness of available antidepressants as well as an understanding of their purported mechanism of action is important.

History

Effective medical treatments for depression have been available since the late 1950s. The earliest forms of 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 have revolutionized 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 (5-HT2) antagonist/reuptake inhibitors (SARIs). These newer agents are currently undergoing clinical trials to assess relative efficacy compared with standard TCAs and SSRIs.

It is notable that antidepressants are useful for many disorders other than depression, especially for anxiety disorders and neuropathic pain. Anxiolysis with antidepressants is discussed in the following sections. The history of antidepressants as analgesics began in 1960, just 2 years after imipramine was reported to be an antidepressant. When first reported to be analgesic, TCAs were thought to work by 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.

Amitriptyline was the first TCA described to have analgesic properties that are independent of antidepressant properties (suggested to relieve migraine via vasodilatory mechanism). There is now a convincing body of controlled data as well as extensive, long-standing clinical experience supporting TCA analgesia that is independent of antidepressant actions. Although SSRIs have been suggested to be useful for pain by anecdotal reports, at present there is no controlled data to support this. The only controlled trial to date did not show independent analgesia.2 Since reduction of depression can reduce pain, separating this antidepressant effect from other intrinsic, independent effects of these drugs is a difficult but critical part of clarifying analgesic effects.

Cyclic Antidepressants (TCAs)

Indications

TCAs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of major depressive disorders and secondary depression in other disorders. Other approved uses of TCAs include treating obsessive-compulsive disorder (clomipramine) and enuresis (imipramine). TCAs are also useful in treating generalized anxiety, panic disorder, agoraphobia, bulimia, attention deficit hyperactivity disorder (ADHD), and chronic pain.

Chemistry

Although this class includes tricyclics and heterocyclics, they are generally referred to as tricyclics (TCAs). They are named for their three-ring structure, that is, two benzene rings connected by a double-carbon bond. The tertiary amines (amitriptyline, imipramine) have two methyl groups on the terminal nitrogen atom of the side chain. Demethylation of these results in the secondary amines nortryptiline and desipramine, respectively. In general, the secondary amines have less anticholinergic side-effects than do the tertiary amines. Table 63-1 lists the common tricyclics divided by secondary and tertiary amine groups.

Mechanism of Action

There exists some question about the precise mechanism of how tricyclics combat depression. All tricyclics inhibit both serotonergic and noradrenergic reuptake; and these effects are seen early, but clinical benefits often begin 2 to 3 weeks after initiation of treatment. In other words, side effects are seen right away, whereas clinical benefits take several weeks to emerge.

This disparity raises questions about the exact relationship between NE/5-HT reuptake inhibition and the antidepressant effects of TCAs. Downregulation of β-adrenergic receptors correlates temporally with onset of action, but this is likely a marker for the role of second-messenger systems and neuronal gene regulation in the therapeutic mechanism of TCAs.

There is no dispute that relief of depression also relieves some chronic pain. Therefore, TCAs relieve pain as an antidepressant, but also may offer independent analgesia, perhaps by other mechanisms such as its blockade of sodium channels rather than by their well-described inhibitory effects on NE/5-HT reuptake. Still, some endorse the idea that because serotonin has been implicated as the major neurotransmitter in descending inhibitory tracts, TCAs relieve pain by making more serotonin available.

TCAs as analgesics rarely offer complete analgesia, and TCA side effects are common due to the antagonist effects on the cholinergic, adrenergic, and histaminergic systems. These agents are compelling analgesics, particularly with comorbid depression or insomnia. Reasonable goals for using TCAs as analgesics include decreased pain intensity from unbearable to bearable. Some mild side effects may be unavoidable in exchange for analgesia.

There are some common misconceptions about TCAs as analgesics. For instance, there probably is not a therapeutic window, whereby analgesia is diminished above and below threshold dosages. Another misconception is that analgesia requires only low dosages of TCA. Evidence suggests that analgesia is maximized with increased doses as well as with time. The time course of analgesic TCAs 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.

Pharmacokinetics

TCAs are typically lipophilic, and thus easily pass through the blood–brain barrier. They are widely distributed in major organs including lung, heart, brain, and liver. Eighty-five to 95% of the drug is protein bound, although individual differences can cause up to a four-fold variation in amount of free drug. All TCAs undergo first-pass hepatic metabolism; intermediate stages involve demethylation, oxidation, and glucuronide conjugation. As mentioned earlier, the demethylated daughter metabolites have fewer side effects. For instance, nortriptyline and desipramine have fewer anticholinergic side effects than amitriptyline and imipramine, respectively. Demethylated metabolites are usually biologically active with plasma half-lives often greater than two times that of the tertiary amine parent compound. Thus, the washout period is usually a week or more.

Because hepatic clearance involves the P450 enzyme system, drug interactions are possible. For example, P450 enzyme inhibitors, such as fluoxetine, cimetadine, and methylphenidate increase TCA plasma levels. P450 enzyme inducers such as phenobarbitol, carbamazepine, and cigarette smoking decrease TCA plasma levels. Decreased gut absorption is also a possible cause of decreased TCA plasma levels and may occur with use of common agents such as cholestyramine.

Combining TCAs with opiate agonists 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.

Phytochemical Reactions

Serotonin syndrome may occur when St. John’s wort is used in conjunction with TCAs (an in vitro study indicated that St. John’s wort affected serotonin reuptake.3 In addition, serotonin is deaminated by MAO type A, and some early studies showed that St. John’s wort inhibits MAO type A.4 Monitor the concurrent use of other phytochemicals such as kava or valerian, which function as central nervous system (CNS) depressants.

Adverse Reactions

In treating depression, all TCAs are considered equally efficacious but have significantly different side-effect profiles. Thus, choosing a particular TCA can be made on the basis of side-effect profile. Some side effects such as sedation may be beneficial to some patients with insomnia.

Before initiating treatment, routine laboratory screening may include complete blood count, electrolytes, BUN, creatinine, and liver function tests. Because tricyclics have quinidine-like properties, can increase all intervals of the electrocardiogram (ECG), and are potentially proarrhythmic, ECG screening may be requested.

As previously described, TCAs interact with multiple neurotransmitter systems and as a result present with a wider side-effect profile than SSRIs. TCAs may manifest all anticholinergic symptoms including dry mucous membranes, blurred vision, constipation, urinary retention, excessive sweating, and confusion or delirium. Antagonism of histaminic receptors may result in sedation, weight gain, or confusion. Cardiovascular effects result from a combination of interactions with α1-adrenergic, muscarinic, serotonergic, and histaminic receptors as well as IA antiarrhythmic actions of TCAs. Cardiovascular side effects include tachycardia, orthostatic hypotension, prolonged cardiac conduction, and arrhythmias. Sexual side effects are also seen with TCAs and include decreased libido, impotence, erectile difficulties, ejaculatory disturbances, and anorgasmia. As with SSRIs, TCAs may cause or exacerbate extrapyramidal symptoms. TCAs likely decrease the seizure threshold as well. Rare side effects include abnormalities in serum glucose levels, syndrome of inappropriate antidiuretic hormone (SIADH), jaundice, hepatitis, blood dyscrasias, and photosensitivity.

Rarely, patients may develop a discontinuation syndrome following abrupt cessation of the TCA. Withdrawal may manifest as anxiety, fever, sweating, myalgia, headache, nausea, vomiting, dizziness, dyskinesia, or akathesia. Overdose with TCAs can be lethal. Toxicity results from anticholinergic effects and 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 and death. Since three to five times the therapeutic dose of TCAs is potentially lethal, this low therapeutic index (ratio of toxic to therapeutic dose) must make prescribers vigilant. This is probably a large part of the reason SSRIs are chosen as first-line antidepressants over TCAs.

Dosages and Monitoring

Although somewhat controversial, it is generally agreed that plasma levels may be clinically useful when using imipramine, desipramine, or nortriptyline. Plasma levels of nortriptyline may be especially useful in that a therapeutic level may exist where levels >150 may be less efficacious than lower levels. As with all antidepressants, effects are often delayed. Antidepressant effects may be seen anywhere from 2 to 6 weeks of a trial at therapeutic dosages. Following effective response, patients should continue the medication for 6 to 12 months to prevent relapse.5 Dosage should not be decreased during the maintenance phase of treatment (Table 63-1). If a patient has had multiple recurrences of their illness, an indefinite length of treatment may be indicated.

Monoamine Oxidase Inhibitors (MAOIs)

Indications

MAOIs are approved for use in major depression, double depression (dysthymia superimposed on major depression), psychotic depression, social phobia, and simple phobias and 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 due to 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 other agents.

Chemistry

MAOIs are divided into hydrazines and nonhydrazines. Hydrazines marketed in the United States include phenelzine (Nardil) and isocarboxazid (Marplan). The nonhydrazine is tranylcypramine (Parnate), which closely resembles the amphetamine structure.

Mechanism of Action

MAOIs work by binding to the enzyme monoamine oxidase, thus inhibiting the breakdown of monamines 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. This increased availability of monoamine is what is believed to alleviate depressive symptoms. It is important to remember that MAO inhibitors block the action of MAO as well as other enzymes, thus causing alterations in the hepatic metabolism of many other drugs.6

MAOIs may be reversible or irreversible, though only irreversible MAOIs are available in the United States. While reversible MAOIs, known as reversible inhibitors of monoamine activity (RIMAs), are widely available outside of the United States, for our purposes, we discuss only irreversible MAOIs.

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 63-2 offers some dosage guidelines for MAOIs. Another significant difference from standard TCAs and SSRIs is that MAOIs have a short half-life and require twice daily dosing. To date, there are no implications of direct analgesic effect by MAOIs. Recall that relief of depression also relieves some degree of pain.

Pharmacokinetics

MAOIs are rapidly and fully absorbed from the gastrointestinal (GI) tract. They are biotransformed in the liver and excreted rapidly. Although their half-life is very short, they have long-lasting pharmacologic effects because they permanently bind to and deactivate enzymes. It takes approximately 2 to 3 weeks for the body to resynthesize monoamine oxidase; therefore, at least that long should be allowed between drug trials.

Adverse Reactions

Sympathomimetic amines such as tyramine exert pressor effects on the human system; when not broken down by MAO, introduction of exogenous tyramines can set off a hypertensive crisis. For this reason, patients taking MAOIs should avoid foods high in tyramine content, such as cheeses, yeast supplements, or aged alcohols. Symptoms of a hypertensive crisis include occipital headache, neck stiffness or soreness, dilated pupils, tachycardia or bradycardia, and constricting chest pain. Because of this risk, MAOIs should be used with caution in patients with cerebrovascular disease, cardiovascular disease, or hypertension.

Although the stimulant effect of MAOIs is often helpful for some patients suffering from major depression, symptoms of insomnia, restlessness, and anxiety, they may be excessive. Other 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 cautiously with MAOIs: Fatalities have been reported from patients taking fluoxetine in concert with MAOIs. Concomitant use of MAOIs with SSRIs runs the risk of developing serotonin syndrome. Symptoms of serotonin syndrome include CNS irritability, myoclonus, diaphoresis, and elevated temperature. Severe cases may result in death. Thus, patients should discontinue MAOIs for at least 2 weeks before beginning an SSRI. Because of its particularly persistent metabolite, fluoxetine requires MAOI discontinuation for at least 5 weeks. Of course, SSRIs must be similarly discontinued for prolonged periods before starting a MAOI. These dietary restrictions should be continued for at least 10 days following discontinuation of the MAOI as a washout period.

Psychostimulants and sympathomimetics should be used cautiously, if at all, in patients taking MAOIs. Avoid using meperidine with MAOIs, as this can cause excessive serotonin concentrations resulting in excitation, sweating, hypertension, respiratory depression, coma, and vasculatory collapse. It is unclear if other opiate agonists have the same adverse pharmacodynamic effects.

Phytochemical Reactions

Any substances that act on the CNS, for example, kava kava, Piper methysticum, or valerian (Valeriana officinalis), should be carefully monitored for MAOI interactions. For the same reason, St. John’s wort (Hypericum perforatum) should not be used with MAOIs.

Dosages and Monitoring

It appears that optimal antidepressant efficacy is seen when MAOIs are given at doses that reduce MAO activity by at least 80% (see Table 63-2 for dosages). 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.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Since the introduction of fluoxetine (Prozac) in 1987, several other selective serotonin reuptake inhibitors (SSRIs) have been introduced and have revolutionized first-line therapy for depression (Table 63-3).

Indications

Although SSRIs were initially introduced for use in major depressive disorder, the FDA has approved other indications for these agents, 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.

Chemistry

SSRIs are structurally diverse.

Mechanism of Action

SSRIs act via specific mechanisms in the central nervous system (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. This delays presynaptic reuptake of serotonin following its presynaptic release. Thus, serotonin persists in the synaptic cleft, able to exert its effects on neurotransmission for a longer duration. These effects occur almost immediately. However, clinical antidepressant response from SSRIs is usually not observed until 2 to 3 weeks following initiation of treatment. Other delayed actions, such as second-messenger effects and neuronal gene regulation, may play a role in the efficacy of SSRIs.

Although there are reports of SSRI-induced analgesia, these are anecdotal. The only controlled trial by Max et al2 did not find these agents to possess independent analgesia. It is important to keep in mind the adage that “absence of proof is not proof of absence,” and there exist those who suggest that the serotonergic mechanisms of descending inhibitory pathways are influenced by more serotonin available in the synaptic cleft.

Pharmacokinetics

SSRIs are metabolized by hepatic oxidation and their use may affect serum levels of other hepatically metabolized drugs. This occurs via induction and inhibition of various cytochrome P450 enzymes. SSRIs may increase levels of tricyclic antidepressants and benzodiazepines as well as other drugs. There may also be effects on levels of carbamazepine, lithium, and antipsychotics. Other serotonergic drugs should be avoided or used with caution given the possibility of causing serotonergic syndrome. There is a report of visual hallucinations in a patient taking fluoxetine, after using dextromethorphan.7 Dextromethorphan is metabolized by the cytochrome P450 enzyme, which is inhibited by fluoxetine. Although this is a single case report, prescribing both simultaneously may require caution.

Phytochemical Reactions

As in other antidepressants or mood stabilizers, caution is advised in combining these with any phytochemicals known to affect mood, such as valerian, kava kava, or St. John’s wort.

Adverse Reactions

Although SSRIs have limited side effects because they have minimal effects on neurotransmitters other than serotonin, 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. There are also conflicting reports regarding SSRIs lowering the seizure threshold. Cardiovascular effects are rare but there are reports of tachycardia, bradycardia, palpitations, and vasoconstriction. Gastrointestinal effects include nausea, vomiting, anorexia, bloating, and diarrhea. Rare side effects include SIADH, jaundice, hepatitis, and bleeding disorders. The limited sedation associated with these agents makes them ideal additions for patients with pain on sedating analgesics.

Lastly, approximately 10% to 15% of patients taking an SSRI will experience sexual side effects. This may manifest as decreased libido, impotence, ejaculatory disturbances, and anorgasmia. Change to another SSRI may alleviate these symptoms. However, if changing SSRIs is not effective, a switch to another class of antidepressants may or may not be necessary. Addition of adjunct agents to treat sexual side effects are often helpful. These adjuncts include amantadine, bethanacol, cyproheptadine, neostigmine, and yohimbine. Coadministration of the antidepressant bupropion (Wellbutrin), discussed in the section on Atypical Antidepressant, may also alleviate sexual side effects and provide additional antidepressant efficacy.

Dosages and Monitoring

Other than to rule out a medical cause of the patient’s symptoms, no initial laboratory workup is required prior to initiate treatment with SSRIs. Although plasma concentrations of fluoxetine plus norfluoxetine above 500 ng/mL seem to be associated with poorer response than lower concentrations, dosage titration is usually based on clinical response and side effects. Note that beneficial effects are usually not seen prior to 2 to 3 weeks.

When SSRIs are discontinued, the dosage should be tapered slowly to avoid withdrawal symptoms. Withdrawal is uncommon and not life-threatening, but it may be unpleasant if it does occur. Withdrawal often includes flulike symptoms including GI upset, vomiting, diarrhea, fever, diaphoresis, irritability, headache, dizziness, and arthralgia. Overdose of SSRIs alone has not been reported to cause death, and the relative safety of SSRIs in this regard contributes to their first-line status in the treatment of depression, where suicide rates may be as high as 10% to 15%. Given the incidence of depression in chronic pain patients, this relative safety offers an advantage over other antidepressants used for pain management. In the event of overdose, symptoms of toxicity include nausea, vomiting, tremor, and myoclonus. Treatment is symptomatic and supportive.

Atypical Antidepressants

Following the introduction of SSRIs, several other classes of antidepressants have been developed. These classes have been designed to target specific neurotransmitter interactions at the synaptic level. They attempt to maximize therapeutic benefits while minimizing side effects. These classes include norepinephrine and dopamine reuptake inhibitors (NDRIs), such as bupropion (Wellbutrin), serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine (Effexor), and 5-HT2 antagonist/reuptake inhibitors (SARIs) represented by trazodone and nefazodone.

Bupropion (Wellbutrin), an NDRI, is a weak inhibitor of noradrenergic and dopaminergic reuptake pumps. However, it is metabolized to hydroxybupropion, which is a powerful inhibitor of both noradrenergic and dopaminergic pumps. This agent differs from most other antidepressants in that it has psychostimulant properties. Thus, as well as being used for depression, it may be useful for treating attention deficit hyperactivity disorder . There have been no 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 moved to twice daily dosing and gradually increased, though 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. Dosages of 450 to 600 mg/day may cause seizures in 4.0% of patients. Therefore, doses 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. Laboratory studies are not necessary before starting bupropion and serum levels are not clinically useful. The most common adverse effects are headache, insomnia, upper respiratory complaints, nausea, restlessness, agitation, and irritability. In overdose, dosages as high as 4200 mg have been taken without death. However, bupropion should not be given with MAOIs, nor in patients with anorexia or eating disorders. Care should be taken when coadministering other drugs that are hepatically metabolized because bupropion is metabolized by the liver.

Venlafaxine (Effexor) is an SNRI that possesses no α1, cholinergic, or histaminic inhibition. Venlafaxine has dose-related degrees of inhibition of serotonin reuptake (most potent at low doses), norepinephrine reuptake (moderate potency at higher doses), and dopamine reuptake (least potent at highest doses). Venlafaxine is indicated for major depression and possibly ADHD. Though there have been no controlled trials, some anecdotal evidence points toward efficacy in the treatment of chronic pain. Potential analgesia is suggested by its profile of dual inhibition of serotonin and norepinephrine reuptake that is similar to proven analgesic antidepressants such as imipramine, amitriptyline, and desipramine. Venlafaxine differs from these agents in its lack of anticholinergic, antiadrenergic, and antihistiminergic side effects, a difference that has unknown bearing on analgesia. Venlafaxine was approved by the FDA in 1999 for treatment of generalized anxiety disorder.

In 1997, an extended-release formulation was approved. Although in traditional form, venlafaxine is 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 not 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 venlafaxine may affect hepatic metabolism of other medications.

Trazodone and nefazodone are SARIs by virtue of blocking 5-HT2 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, though 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 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 (1/1000 to 1/10000), 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. Lastly, SARIs may increase serum levels of triazolam (Halcion) and alprazolam (Xanax).

Description

Antipsychotics are used to treat various psychoses and schizophrenia. They also are used to treat psychotic symptoms such as in 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 their potentially permanent side effect of tardive dyskinesia make such a chronic usage inadvisable.

Psychotic has many different meanings in many different contexts. Conceptually, it refers to impairment in reality testing. Early definitions (The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. [DSM-II]) of psychotic referred to mental “impairment that grossly interferes with the capacity to meet ordinary demands of life.” Across the spectrum of DSM-IV psychoses, the term refers to delusions, hallucinations, disorganized speech, and catatonic behavior. Incidence is estimated to be approximately 1 in 10,000 per year in the diagnosis of schizophrenia, schizophreniform disorder, and schizoaffective disorder. Delusional disorder prevalence estimates are around 0.03%.

History

Antipsychotics, also known as neuroleptics or major tranquilizers, were introduced in the 1950s, initiating the contemporary field of psychopharmacology. Such “major tranquilizers” offered more than just sedation to patients, they helped clear cognitive processes and allowed more patients to spend less time institutionalized. Unfortunately, these new medications produced neurologic side effects that were often irreversible. For this reason they were called neuroleptics.

The experience of pain is rife with nociceptive and non-nociceptive aspects, and it is usually difficult to distinguish pain from suffering. Although neuroleptic agents possess some degree of independent analgesia, their significant and potentially irreversible side effects undermine their use in the treatment of chronic pain. However, these agents can have a role in chronic pain when used for short periods. 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 may offer coanalgesia in select cases.

Some antipsychotics, including haloperidol, have a molecular structure similar to that of morphine or meperidine. Cautious and short-term use of neuroleptics in the patient in pain may be indicated when thought disorder is present or when fearfulness is not responding to other agents such as benzodiazepines. Since most analgesics can be potential culprits in the onset of delirium, it is important that the pain specialist be able to recognize delirium and treat it effectively. Treatment of delirium usually involves removing or resolving underlying causes. Neuroleptics may be invaluable for short-term management when other analgesic agents have produced delirium. Moreover, neuroleptics can be extremely useful in critical-care situations when sedation is required without either respiratory or hemodynamic depression.

Typical Antipsychotics

Indications

Antipsychotics are approved to treat psychiatric symptoms and schizophrenia.

Chemistry

There exists several chemical classes of neuroleptics: phenothiazines, thioxanthenes, butyrophenones, dibenzoxazepines, and dihydroindolones. The largest group—the thioxanthenes—are tricyclic, consisting of two benzene molecules connected by a sulfur and nitrogen.

Mechanism of Action

Typical neuroleptics (Table 63-4) 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 temporal and frontal lobes. Typical neuroleptics also may affect cholinergic, α-1 adrenergic, and histaminic systems. These actions are responsible for many of the considerable side effects of typical neuroleptics.

Pharmacokinetics

Antipsychotic drugs are highly lipophilic and thus pass easily through the blood–brain barrier. They bind tightly to body membranes and proteins. Although plasma half-life is usually 10 to 20 hours, half-life with the central nervous system is probably longer, based on the drug’s effects. Plasma serum levels are not well correlated with clinical efficacy. Antipsychotics may potentiate postural hypotension associated with antihypertensive drugs (often used for vasodilatation in reflex sympathetic dystrophy (RSD) or RPS).

Phytochemical Reactions

Various phytochemicals may interact with anticholinergic medications. Those that may potentiate effects include black haw, bogbean, buchu, catsclaw, chamomile, chondroitin, deadly nightshade, and jimsonweed. Those that may depotentiate effects include jaborandi tree and pill-bearing spurge.

Adverse Reactions

Antipsychotics carry 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 including amenorrhea, galactorrhea, and false-positive pregnancy tests in women and gynecomastia and galactorrhea in men. Neuroleptics may cause hypothalamic dysfunction (leading to SIADH and temperature regulation difficulties) or disrupt serum glucose levels. Neuroleptic malignant syndrome is a particularly serious, albeit rare, potential adverse 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 α1-adrenergic effects may cause sexual dysfunction. In addition, neuroleptics may lower the seizure threshold, seen most in lower potency agents such as thorazine and least in high potency agents such as haloperidol. Cardiovascular effects include hypotension, tachycardia, dizziness, fainting, nonspecific CG changes, and rarely arrhythmias, including “torsades de pointes” and sudden cardiac death.

Dosages and Monitoring

No routine laboratory tests are necessary for the prescribing of antipsychotic agents (see Table 63-4 for dosing). Be aware of the emergence of extrapyramidal side effects—and warn patients about potential tardive dyskinesia.

Atypical Neuroleptics

Atypical neuroleptics include agents such as risperidone (Risperdal), clozapine (Clozaril), and the recently released olanzipine (Zyprexa). These agents have D2 antagonism, but to a lesser degree than typical neuroleptics. Additionally, they appear to block 5-HT2 receptors, and to variable degrees, the D4 receptor. Atypical neuroleptics may be more efficacious than typical neuroleptics, particularly with negative psychotic symptoms (Table 63-5). 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.

Clozapine is a dibenzodiazepine derivative, structurally similar to loxapine. Clozapine is considered a second-line treatment for patients due to the possibility of fatal agranulocytosis in about 1% of exposed 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 olanzepine. Risperidone also has reduced incidence of extrapyramidal side effects, and like olanzepine, is not associated with agranulocytosis. Olanzapine appears to be more sedating than risperidone; risperidone can cause insomnia.

Description

Mood stabilizers are used to treat bipolar disorder, a condition that involves alternating periods and degrees of mania and depression. The mood stabilizer levels out the phasic mood fluctuations. Bipolar disorder prevalence in community samples is 0.4% to 1.6%. Cyclothymia (less severe mood fluctuations) prevalence rates are similar: 0.4% to 1%.

History

Lithium is the classic agent for treating bipolar disorder. It has been used medicinally since the 1800s, but not until 1949 did the Australian Cade notice it had a calming effect on agitated psychiatric patients. Recently, however, many other agents such as anticonvulsants (valproic acid, carbamazepine, gabapentin, and clonazepam) have gained popularity in the treatment of bipolar conditions. The overlap of this group of drugs with those used to treat neuropathic pain is striking and its meaning has not yet been clarified.

While bipolar disorder is not overly common in the patient with chronic pain, it does occur and can be worsened by drugs that are commonly used in the pain arsenal. 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 obvious 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 common agent used for treating bipolar disorder. A narrow therapeutic index and 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.

Indications

Valproic acid is approved for the treatment of bipolar disorder and migraine prevention. Carbamazepine is used to treat mood disorders, disruptive behavior in dementia, neuropathic pain, postherpetic neuralgia, and diabetic neuropathy.

Chemistry

Lithium is an alkali metal. Gabapentin is a GABA molecule bound to a cyclohexane ring, whereas valproic acid is a simple branched-chain carboxylic acid. Carbamazepine is chemically and structurally related to the tricyclic antidepressants.

Mechanism of Action

The mechanisms of action of this diverse group are understandably varied, but all are thought to act as membrane stabilizers. Phenytoin and carbamazepine both slow the rate of recovery of voltage-activated Na+ channels from inactivity. Clonazepam stimulates GABAergic pathways, valproic acid is believed to increase GABA concentrations in the brain, whereas gabapentin’s action is unknown. Although it functions as a GABA analogue, gabapentin does not act at GABA receptors. The action of lithium’s therapeutic effects is unknown, but postulated to be either endocrine, neurotransmission, circadian, or cellular. Lithium is not a sedative, depressant, or euphoriant.

Pharmacokinetics

Lithium is absorbed almost completely from the GI tract in 8 hours, and peaks in 2 to 4 hours. Slow release preparations are available. Elimination half-life is 20 to 24 hours.

Valproic acid is absorbed almost completely from the stomach with peak concentrations in 1 to 4 hours. Almost 90% of the drug is protein bound. Half-life is about 18 hours. Periodic laboratory monitoring during use renders valproate more cumbersome to use than other neuropathic analgesics. Patients should have CBC and liver function tests before initiating treatment. Starting dosage is typically 250 mg/day, with gradual increases until therapeutic serum levels and clinical response occur. Possible side effects include blood dyscrasias (though less common than with carbamazepine) and hepatitis.

Gabapentin is rapidly absorbed and is not metabolized or protein bound; it is excreted in the urine. Half-life is about 5 to 9 hours and it is highly lipid-soluble.

Carbamazepine is absorbed slowly and erratically. Peak plasma concentrations are seen at about 4 to 8 hours; it is 75% protein bound. Half-life is 10 to 20 hours. The immediate metabolite 10,11 epoxide is as active as the parent compound. Because carbamazepine is hepatically metabolized, it may affect the metabolism of other drugs as well. In addition, there have been reports of carbamazepine-induced hepatitis. Electrolyte disturbances, especially hyponatremia and SIADH, may occur. For these reasons, follow-up laboratory studies should be conducted periodically. When beginning treatment with carbamazepine, CBC should be obtained every 2 weeks for the first 2 months of treatment and quarterly thereafter. The initial laboratory workup should include CBC, liver function tests, electrolytes, and ECG.

Although carbamazepine may be effective in the treatment of chronic pain and it is relatively safe, one may want to use it as a second-line neuropathic analgesic because of the extensive laboratory studies that are required. In addition to its usefulness as an anticonvulsant, carbamazepine is used by psychiatrists in the treatment of bipolar disorder as well as for aggressive behavioral disorders. Its mechanism of action in the treatment of mania or depression is unclear. Patients are usually started at a dose of 200 mg twice daily and the dose is gradually increased until plasma levels are therapeutic and adequate clinical response is achieved. The most concerning potential side effect is blood dyscrasia, including agranulocytosis.

Clonazepam plasma concentrations peak in about 1 to 4 hours after oral administration. It is highly lipid-soluble and binds to plasma proteins. Half-life is about 1 day; clonazepam is metabolized by nitro-group reduction.

Phenytoin absorption is slow and variable. Plasma concentrations peak anywhere from 3 to 12 hours; it is 90% plasma protein bound.

Description

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—praumatic 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.

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. Why clonazepam is used over other benzodiazepines is controversial.

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.

Chemistry

Benzodiazepines are so named because they consist of a benzene ring connected to a seven-membered diazepine ring. Various derivatives produce similar effects.

Mechanism of Action

All benzodiazepines share the same mechanism of action. Benzodiazepines depress the CNS at the levels of the limbic system, brainstem reticular activating formation, and cortex. They bind to the benzodiazepine component of the GABA receptor and facilitate the action of GABA, an inhibitory neurotransmitter. They bind tightly to plasma protein, are highly lipophilic, and resistant to removal through dialysis.

Although not primary analgesics, benzodiazepines often have a role in the analgesic regimen. Clonazepam (Klonopin) may possess special neuropathic analgesic properties; however, this has yet to be confirmed by controlled trials.

Pharmacokinetics

The choice of a specific benzodiazepine is often based on onset of action and half-life (Table 63-6). In general, short-acting agents are used to treat insomnia and acute anxiety, whereas long-acting agents are used to treat chronic conditions.

Adverse Reactions

The most common side effect of benzodiazepines is sedation and respiratory depression. A paradoxical reaction is also possible where a patient may become increasingly agitated and disinhibited. Although possibly difficult to recognize, if this occurs, cessation of the benzodiazepine is indicated rather than increased dosage. Rapid withdrawal from benzodiazepines can result in rebound insomnia, anxiety, delirium, or withdrawal. Severe withdrawal reactions include seizures, psychosis, and death. Therefore, it is important to discontinue dosages by gradual taper.

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.

Buspirone

Although not known to be efficacious for the treatment of pain, buspirone (Buspar) can be an effective anxiolytic. Buspirone does not interact with GABA receptors directly, but instead acts as a 5-HT1A agonist. It is not clear how this action contributes to its anxiolytic effects. Buspirone is an especially useful anxiolytic in patients with a history of substance abuse or who may abuse benzodiazepines. In addition, buspirone may potentiate the antidepressant and anti-obsessional effects of SSRIs and is also being studied for use in post-traumatic stress syndrome. 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 daily. Unlike benzodiazepines, anxiolytic effects are not immediate, requiring 1 to 4 weeks for anxiolytic effects to appear. Fortunately, buspirone has relatively few side effects. Potential side effects include headache, dizziness, lightheadedness, fatigue, parasthesias, and GI upset, although all of these occur in less than 10% of patients. Buspirone has a low potential for abuse or addiction and it does not impair psychomotor or cognitive functions. This feature makes it a useful agent for the anxious patient in pain with a history of addiction. 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.

Treating pain often requires use of medications that affect both nociceptive and non-nociceptive processes. Without adequate familiarity of psychopharmacologic agents, the pain specialist risks limiting her or his analgesic repertoire. He or she may overlook potentially beneficial possibilities as well as potential adverse complications of polypharmacy. The ongoing revolution in development of psychoactive drugs will surely have an impact on pain management, and drugs will likely gain increased prominence in the arsenal against pain.