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5 Articles in Volume 3, Issue #1
A Conceptual Model of Pain: Treatment Modalities
Antidepressants in Pain Treatment
Choosing the Right Triptan
Massage Therapy and Pain Management
Minimally Invasive Spine Interventions

Antidepressants in Pain Treatment

General guidelines in the selection of an antidepressant as an adjunct to analgesia and physical therapy in treating pain.

Depression is a virtually universal complication of intractable pain. When pain prevents patients from doing the things that give them satisfaction and purpose in life, depression is unavoidable. Antidepressants have become a routine adjunctive therapy for most forms of chronic pain.1-6 Not only may they provide their primary mission of mood elevation, they may also have other positive attributes including relief from neuropathic pain, headache prophylaxis, sleep induction, and potentiation of opioid therapy. But how does a practitioner select the “right” one considering that there are now over 20 antidepressants on the commercial market with more to come? At this point in time there is insufficient clinical experience to establish reliable selection criteria. However, some general guidelines are presented here that may be useful until controlled studies provide more specific guidelines.

Select one with which you are familiar

Antidepressants may all produce profound side-effects including complications such as cardiac arrhythmias, blurred vision, dystonia, psychosis, over-sedation, weight gain and sexual dysfunction. Keep in mind that the terms “antidepressant” and “mood elevator” are unfortunately vague. In fact “antidepressants” vary widely as to their effect on neurotransmission and should scientifically be labeled according to their selective effect on adrenergic receptors, serotonin reuptake, monoamine oxidase and other neurotransmitters and receptors. Knowing the psychopharmacological consequences of these effects provides a scientific basis for drug selection. Generally speaking, however, there are four classes from which to choose:

  1. Monoamine oxidase inhibitors. These very old drugs should be left to experienced clinicians for special situations, as they are potentially fatally toxic.
  2. Tricyclics. These include amitriptyline, imipramine, and desipramine and are also very old and often most familiar to non-psychopharmacologists. They cause more adverse effects and complications than newer agents, particularly weight gain, dry mouth, sedation, sexual dysfunction, lethargy, and cardiotoxicity in overdoses. Other than inexpensiveness, there is no reason to favor this group over other antidepressants.
  3. Serotonin reuptake inhibitors (SRI). These agents are the most popular antidepressants. They slow absorption of the neurotransmitter serotonin. They do not have significant cardiac effects and are generally safer that tricyclics. Although not studied as well in pain states as the tricyclics, early clinical reports suggest that they may be effective in a wide variety of pain problems.3,6
  4. “Multiple action” agents. These include trazodone, nefazodone, and mirtazapine and are often effective when SRIs have failed, because these agents affect more than one receptor or neurotransmitter system. In some cases, the precise biochemical mechanism by which they act is not well understood. Some agents such as venlofaxine and bupropion have considerable stimulation and anti-fatigue effects presumably because they increase norepinephrine activity.5 In some patients, however, they cause weight gain, sexual dysfunction, or paradoxical effects such as excess stimulation or sedation.

It is important to know that side-effects of all antidepressants may be dose dependent. It is always best to start at a minimum dose and titrate upwards gradually and patiently. Dosage increase should not exceed about 25% a week, on the average, while seeking to reach a therapeutic dose in about a month. It is helpful to monitor the patient’s weight at each follow up visit, and to alert the patient to be aware of various potential adverse effects and to report these immediately.

Finally, as non-psychopharmacological specialists, there is a natural tendency to rely first on drugs with which you have the most experience. But this should not result in avoidance of the newer agents. With experience, a practitioner may find that many different antidepressants can become part of his/her armamentarium for treating pain. Tolerance does occur occasionally, but generally only after months of continued treatment. In these cases, a trial of an agent from a different class is logical. In treatment-resistant cases, combinations of agents may be required but these are best managed by physicians with extensive experience.

Patient Requests

In this day and age of direct consumer advertising of prescription pharmaceuticals and the emerging self-help movement of pain patients, a patient may request a specific antidepressant. The patient may even know the starting dose and the drug’s potential side-effects. It is certainly proper to respond to a patient’s request for a medication, as long as the request is reasonable and medically indicated given the patient’s unique circumstances. If, for example, the patient had previously had treatment failures with several SRIs and requests a different SRI based on an advertisement, that would not be sufficient reason to indulge that particular patient. This is where the physician’s expertise would be most helpful.

Chronic pain patients may have unusual, clinical circumstances. They are likely to have already been treated with multiple medications which have significant side-effects. Consequently, a drug interaction such as over-sedation or psychosis can occur when an antidepressant is added to a regimen of multiple treatment agents.

Fitting an Agent to the Problem

As discussed above, antidepressants can be classified by their primary neurochemical effect and class of action. Table 1 lists antidepressants commercially available in the United States and the starting range of dose. It is recommended that the starting dose be low, and slowly titrated upward over time. No single antidepressant has been found to be superior in the treatment of pain. But an appropriate match of an antidepressant’s clinical profile with the patient’s presenting symptoms is logical. The clinician should determine the goal of treatment such as sleep induction or opioid potentiation in selecting an antidepressant. If, for example, insomnia and other sleep disturbances are present, the use of trazodone or nefazodone which are known for their ability to induce physiologically normative sleep would be a logical choice. Similarly, if low energy, excessive sleepiness, fatigue, attention deficits, and opioid somnolence are significant symptoms, an activating antidepressant such as desipramine, bupropion, or venlafaxine would be a logical first selection.

Summary of Commercially Available Antidepressants
Drug by Category Starting Dos (mg)
Amitriplyline (Elavil®) 25 - 50
Clomipramine (Anafranil®) 25 - 50
Doxepin (Sinequan®) 25 - 50
Imipramine (Tofranil®) 25 - 50
Trimipramine (Surmontil®) 25 - 50
Desipramine (Norpramin®) 25 - 50
Nortriptyline (Pamelor®) 25 - 50
Protriptyline (Vavactil®) 25 - 50
Monoamin Oxidase Inhibitors
Phenelzine (Nardile®) 15 bid
Tranylcypromine (Parnate®) 10 bid
Isocarboxazid (Marplan®) 10
Serotonin Reuptake Inhibitors
Fluoxetine (Prozac®) 20
Paroxetine (Paxil®) 20
Sertraline (Zolofte®) 50
Fluvoxamine (Lovox®) 50
Citalopram (Celexa®) 20
Escitalopram (Lexapro®) 10
Multiple Action Agents
Bupropion (Wellbutrin®) 100
Venlafaxine (Effexor®) 37.5
Nefazodone (Serzone®) 100 bid
Mirtazapine (Remeron®) 15
Reboxetine (Vestra®) 4 bid
Amoxapine (Asendin®) 25 - 50
Maprotiline (Ludiomil®) 75
Trazodone (Desyrel®) 50


Although there have been traditional claims that tricyclics are particularly helpful in treating post-herpetic neuralgia and other peripheral neuropathies, no reliable scientific evidence exists to support a bias for this class over others.1-4 Most importantly, aside from prejudices, the antidepressant that works most effectively to relieve the patient’s symptoms is the drug that should ideally be used. The SRIs have been anecdotally reported to potentiate opioids and to relieve muscle pain in such common conditions as fibromyalgia.3,6 Despite this general observation, all the antidepressants, regardless of class, have the potential to be effective adjuncts to specific pain treatment approaches such as physical therapy and opioid analgesia.

Over-Promise and the Future

All antidepressants should be viewed as adjuncts to specific pain treatment approaches such as physical therapy and analgesia. While a great assist to intractable pain treatment, no antidepressant has yet demonstrated enough acute or chronic pain relief to warrant any promise of substitution for standard pain treatments such as opioids. Practitioners should educate pain patients that antidepressants, used as adjuncts to standard pain treatment, are used “off-label” or other than approved use by the U.S. Food and Drug Administration. Investigation with antidepressants is a fertile ground for pain research. For example, there are no controlled studies on the use of monoamine oxidase inhibitors in pain treatment. The unique neurochemical effects of some antidepressants will undoubtedly prove to have specific uses in pain treatment.


Even though antidepressants are used routinely in pain treatment, there is not yet enough scientific evidence to recommend one antidepressant over another. It is recommended that the practitioner initiate treatment with an agent with which he/she is most familiar, and proceed on the basis of clinical outcome. Table 2 presents a summary of guidelines for the adjunct use of antidepressants.

Guidelines for Antidepressant Use in Pain Treatment

Determine goals of treatment

Select a familiar antidepressant

Start at low dosage and titrate upward
over time

Inform patient about "off-label" use

Do not over-promise results

Switch to a different agent if current
one is ineffective or has side-effects


Last updated on: January 6, 2012
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