Psychopharmacology for the Pain Specialist

Daniel M. Rockers

Karla Hayes

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.

—Paul Briquet in “Traite clinique et therapeutique de l’hysterie”

Knowledge of psychopharmacology is important for a pain practitioner because of the substantial overlap of psychiatric diagnoses with chronic pain conditions as well as the common psychopharmacologic medication groups used as analgesics. Many of these agents have multiple mechanisms of action, accounting 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, followed by anxiolytics and psychostimulants.

I. ANTIDEPRESSANTS

In many chronic pain cases, a patient either will be prescribed an antidepressant or will already be taking one. Antidepressants often serve a dual role: treating a mood disorder and independently addressing pain symptoms.

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 (5HT) reuptake. These antidepressants 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. 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 antagonist/reuptake inhibitors (SARIs). These newer agents are currently undergoing clinical trials to assess relative efficacy compared with standard TCAs and SSRIs. When first reported as having analgesic activity, antidepressants were thought to work by relieving the depression component of pain. Although it is well known that relieving depression by any method is likely to decrease pain, some antidepressants appear to have analgesic properties of their own. A third mechanism to consider is the potentiation or enhancement of opioid analgesia by modulating serotonergic, noradrenergic, and cholinergic effects.

1. Cyclic Antidepressants

(i) 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. In treating chronic pain, they are considered to have independent analgesic effects. Reasonable goals for using TCAs as analgesics include decreasing pain intensity from unbearable to bearable. Some mild side effects may be unavoidable in exchange for analgesia.

(ii) Mechanisms

All TCAs inhibit both serotonergic and noradrenergic reuptake to varying degrees. The tertiary amines have a broader spectrum of activity than the secondary amines. 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.

(iii) Adverse Effects

Unfortunately, the TCAs interact with multiple neurotransmitter systems and, as a result, have a wide side effect profile, including anticholinergic (constipation and dry mouth) and cardiovascular (hypotension and tachycardia) effects. Other effects include sedation, weight gain, and sexual dysfunction. Amitriptyline and the other tertiary amines have more side effects than nortriptyline and the other secondary amines. Caution is advised when prescribing this class of medications to the older patients (because of potential orthostasis leading to falls), patients with closed-angle glaucoma, those with heart block, arrhythmia, or recent myocardial infarction (TCAs are antiarrhythmic, decrease contractility, and increase conduction delays), or patients with suicidal ideation (TCAs can be fatal if overdosed). TCA overdose is a leading cause of drug-related overdose and death. 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.
The low therapeutic index of TCAs is probably a large part of the reason that SSRIs are often chosen as first-line antidepressants over TCAs.

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.

(iv) Dosages and Monitoring

As a general principle, dosing should start at the low end of the dosage range and should be titrated upward in 10- to 25-mg weekly increments until a therapeutic level is reached. This dosing will minimize side effects, and patients will be less likely to reject the therapy because of side effects (see Table 1 for dosages).

2. Monoamine Oxidase Inhibitors

MAOIs (see Table 2) are rarely used anymore because of their potentially serious side effects. They are still prescribed by some psychiatrists to treat patients who have not responded to the other classes of antidepressants. Physicians who do not have training in psychiatry are advised to avoid this class of medications. Phenelzine has been shown to have adjuvant analgesic properties in patients with chronic fatigue syndrome, atypical facial pain, and migraines.

3. Selective Serotonin Reuptake Inhibitors

(i) Indications

Since the introduction of fluoxetine (Prozac) in 1987, several other SSRIs have been introduced and have revolutionized first-line therapy for depression (see Table 3). Although SSRIs initially were introduced for use in major depressive disorder, the US FDA has approved other indications for these agents, including anxiety disorders, 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.

(ii) Mechanisms

The immediate effect of the SSRIs on the central nervous system (CNS) is blockade of the presynaptic serotonin reuptake pump. There have not been many studies examining the efficacy of SSRIs as analgesics. Of 20 studies examining the effect of SSRIs on pain, 12 found that SSRIs provided clinically important pain relief. When SSRIs were compared to TCAs, the latter were shown superior as analgesics in four out of six trials.

(iii) Adverse Reactions

Although SSRIs have fewer side effects than the older antidepressants, they may still cause some undesirable symptoms. Possible CNS effects include headaches, stimulation or sedation, fine tremor, and akathisia. Gastrointestinal effects include nausea, vomiting, anorexia, bloating, and diarrhea. The limited sedation associated with these agents makes them ideal for patients

with pain on sedating analgesics. Other serotonergic drugs should be avoided or used with caution given the possibility of causing serotonergic syndrome. Approximately 10% to 15% of patients taking an SSRI will experience sexual side effects of decreased libido, impotence, ejaculatory disturbances, and anorgasmia.

Table 1. Tricyclic antidepressants

Medication	Proprietary Name	Dosage Range (mg/d)	Anticholinergic Activity	Central Action	Hypotension	Sedation
Tertiary amines
Imipramine	Tofranil	10–300	Moderate	N/S	Moderate	Moderate
Amitriptyline^a	Elavil	10–300	Strong	S(N)	Strong	Strong
Clomipramine	Anafranil	25–300	Moderate	S(N)	Strong	Mild
Doxepin	Sinequan	10–300	Moderate	S	Strong	Mild
Secondary amines
Desipramine^a	Norpramin	10–300	Minimal	N	Mild	Minimal
Nortriptyline^a	Pamelor	10–200	Mild	N/S	Moderate	Mild
Protriptyline	Vivactil	10–60	Moderate	N	Minimal	Mild
Amoxapine	Asendin	50–400	Minimal	N	Mild	Minimal
S, serotonergic; N, norepinephrinergic; (N), weakly norepinephrinergic quantitative sensory testing. ^a Commonly used for neuropathic pain.

Table 2. Monoamine oxidase inhibitors

Medication	Proprietary Name	Dosage Range (mg/d)
Isocarboxazid	Marplan	30–50
Phenelzine	Nardil	45–90
Tranylcypromine	Parnate	20–60

(iv) Dosages and Monitoring

No initial laboratory workup is required. Dosage titration is usually based on clinical response and side effects. Note that beneficial effects are usually not seen before 2 to 3 weeks. When discontinuing SSRIs, taper dosages slowly to avoid withdrawal symptoms.

4. Atypical Antidepressants

Other classes of antidepressants have been developed to target specific neurotransmitter interactions at the synaptic level (see Table 4). These classes of antidepressants maximize therapeutic benefits while minimizing side effects. NDRIs such as bupropion (Wellbutrin), SNRIs such as venlafaxine (Effexor) and duloxetine (Cymbalta), norepinephrine antagonist/serotonin antagonist (NASAs) such as mirtazapine (Remeron), and SARIs, represented by trazodone (Desyrel), are included in these classes (see Table 4 for dosages).

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