Adjuvant Analgesics

CHAPTER 37 ADJUVANT ANALGESICS

Brian Thiessen, MD, Russell K. Portenoy, MD, Charles E. Argoff, MD

1. What are adjuvant analgesics?

Adjuvant analgesics (Table 37-1) are drugs that have primary indications other than pain but are analgesic in some painful conditions. This definition distinguishes a very diverse group of drugs from the traditional analgesics, which comprise the nonopioid analgesics (acetaminophen and the nonsteroidal antiinflammatory drugs) and the opioid analgesics.

TABLE 37-1. Adjuvant Analgesics: Major Classes

Multipurpose Analgesics	Analgesic Agents for Neuropathic Pain Syndromes	Analgesic Agents for Musculoskeletal Pain Syndromes
Antidepressants	Antidepressants	Muscle relaxants
Alpha-2 adrenergic agonists	Anticonvulsants	Benzodiazepines
Corticosteroids	GABA agonists	Analgesic agents for bone pain
Topical anesthetics	Oral local anesthetics Topical anesthetics Sympatholytics NMDA receptor blockers Calcitonin	Corticosteroids Osteoclast inhibitors Radiopharmaceuticals

GABA = gamma-aminobutyric acid, NMDA = N-methyl-D-aspartic acid.

2. For whom and in which situations are adjuvant analgesics appropriate?

To manage pain that is refractory to the traditional analgesics

To allow reduction in dose of the traditional analgesic for the purpose of lessening side effects

To concurrently treat a symptom other than pain

In some clinical settings, adjuvant analgesics have become so well accepted that they are administered as the first-line drug. This is particularly true for chronic neuropathic pain syndromes unrelated to cancer, such as postherpetic neuralgia, trigeminal neuralgia, or painful polyneuropathy (see Question 25). In these situations, the term adjuvant is a misnomer.

3. What factors should be considered prior to prescribing an adjuvant analgesic?

The physician must be aware of the drug’s clinical pharmacology and its particular use in patients with pain. Learn the following about the analgesic:

Approved indications

Unapproved indications widely accepted in medical practice

Common side effects and uncommon, but potentially serious, adverse effects

Important pharmacokinetic features, including half-life, usual time-action relationships, extent of interindividual variability, and factors that may alter disposition (e.g., age or interactions with other drugs)

Specific dosing guidelines for pain

4. What are the special considerations for the older person?

In the medically frail and the older population, a cautious approach to the use of the adjuvant analgesics is warranted. It is prudent to select a drug with a good safety profile and begin therapy at a relatively low dose. Gradual escalation of the dose is the safest technique for confirming an effective regimen or determining that the drug is ineffective.

5. Are responses to the adjuvants uniform?

No. There is considerable interindividual and intraindividual variation in the response to adjuvant analgesics. This variation underscores the potential utility of sequential drug trials, which may be needed to identify a drug with a favorable benefit-to-risk ratio. Moreover, most trials benefit from the use of gradual dose escalation to identify the most optimal dose.

Explain dose escalation and the potential need for multiple trials to patients who are about to begin therapy with an adjuvant analgesic. The information will help the patient maintain appropriate expectations and will reduce frustration during a period of ineffective dosing.

6. Which classes of adjuvant analgesics may be considered multipurpose, nonspecific analgesics?

Adjuvant analgesics that have been demonstrated to be effective in diverse pain syndromes can be designated multipurpose analgesics. The best characterized of these drugs are the tricyclic antidepressants (TCAs). Other classes that can be considered multipurpose include the alpha-2 adrenergic agonists (e.g., clonidine) and the corticosteroids. Although there is some evidence to support the labeling of local anesthetic drugs in this way, conventional practice now limits the use of this class to patients with neuropathic pain syndromes (see next question).

7. What is the evidence that antidepressant drugs are multipurpose analgesics?

Antidepressant drugs, especially the TCAs, have been extensively evaluated in many different pain syndromes, including neuropathic pain, low back pain, headache, fibromyalgia, arthritis, cancer pain, and others. They have been found to have multipurpose analgesic effects. A trial of an analgesic antidepressant is warranted in most patients with chronic pain.

8. Which antidepressants are recommended for chronic pain?

The tertiary amine compound amitriptyline has been best studied, but there is evidence supporting the analgesic efficacy of other tertiary amine tricyclic drugs as well, including imipramine, clomipramine, and doxepin. Of the secondary amine tricyclic compounds, which are generally better tolerated than the tertiary amine drugs, desipramine has been most carefully studied, and nortriptyline is also probably analgesic. Compared with the tertiary amine drugs, these secondary amine compounds are less likely to produce sedative, anticholinergic, or hypotensive side effects. (However, see Question 9.)

Among the newer classes of antidepressants, analgesic effects have been noted for the serotonergic noradrenergic reuptake inhibitors (SNRI) agents duloxetine, venlafaxine, and milnacipran. Duloxetine is in fact approved by the Food and Drug Administration (FDA) for diabetic peripheral neuropathic pain and fibromyalgia. Milnacipran is available in Europe but not in the United States. Analgesic effects have been suggested for bupropion, trazodone, maprotiline, and paroxetine, which is a selective serotonin reuptake inhibitor (SSRI). Of these newer classes, the SSRIs and SNRIs are usually better tolerated than the TCAs.

9. What is the relative analgesic efficacy of the various antidepressant classes?

There have been few studies directly comparing the analgesic efficacy of the various antidepressant drugs. From the very limited data available, an analgesic response is most likely to be produced by the tertiary tricyclic drugs; amitriptyline is preferred because of the extensive data available for this drug. The secondary amine tricyclic drugs, such as desipramine, are probably less analgesic than the tertiary amine drugs, but are more likely to be effective than the SSRIs. But SSRIs have fewer side effects than either secondary or tertiary amines (Table 37-2). Based on this information, the clinician should attempt to select the drug most likely to provide benefit and be tolerated by the patient.

TABLE 37-2. Comparison of Antidepressant Side Effects

10. Do the monoamine oxidase inhibitors have analgesic effects?

The monoamine oxidase inhibitors (MAOIs), such as phenelzine and tranylcypromine, have been evaluated as analgesics in relatively few clinical settings. In a controlled trial, phenelzine was analgesic in patients with atypical facial pain, and a few uncontrolled trials suggested analgesic properties in other types of chronic pain. Despite these findings, use of MAOIs as analgesics has been limited because of the risk of hypertensive crises and the need for significant dietary restrictions.

11. True or false: Relief of depression and analgesia are codependent

False. Relief of depression is not required for the analgesia produced by antidepressant drugs, although improvement in mood no doubt plays a role in some patients. The analgesia produced by the TCAs occurs at a dose significantly lower than that required to treat depression and usually appears within 1 week after this dose is reached—much sooner than the antidepressant effects typically appear.

12. What mechanisms may be responsible for antidepressant analgesia?

The primary pharmacologic action of the antidepressants is to block reuptake of monoaminergic neurotransmitters (e.g., serotonin and norepinephrine) in the central nervous system. Descending pain modulatory pathways that use serotonin and norepinephrine as neurotransmitters have been well characterized, and altered activity in these pathways could be the mechanism by which these drugs yield analgesic effects. The TCAs also interact with many other receptors, some of which have been implicated in other pain-modulating systems.

Interestingly, recent studies have shown that the SSRIs do not yield as much analgesia as the TCAs in patients who are not depressed. The so-called dirty drugs (those affecting multiple receptors, such as TCAs) may exert their effects through multiple systems.

13. What are the adverse effects of the antidepressants?

The secondary amine TCAs are less toxic than the tertiary amine compounds, and the SNRIs and SSRIs are less toxic than either tricyclic subclass (see Table 37-2). At doses commonly used for pain control, the tricyclic compounds have few serious adverse effects. Cardiovascular toxicity, including hypotension and cardiac arrhythmia, is the most serious concern. Significant heart disease, including conduction disturbances, arrhythmias, or heart failure, is a relative contraindication to treatment. Secondary amine compounds, SNRIs, and SSRIs have a lower incidence of cardiotoxicity and are preferred if cardiac disease is present.

The more common side effects of the TCAs are less serious. Anticholinergic effects include dry mouth, urinary retention, blurred vision, and constipation. Somnolence and mental clouding are often transient but are a particular problem in the older person.

Nausea is usually the most common side effect of the SSRIs. Some patients report tremulousness or insomnia, and some experience somnolence. Sexual dysfunction can be a problem for others.