Antidepressants in chronic pain syndromes
K. Ranga Rama Krishnan
Antidepressants in Chronic Pain Syndromes Antidepressants are often effective in the management of chronic pain syndromes. They are most useful for certain types of pain complaints, such as headache, diabetic neuropathy, arthritis and facial pain. The choice of antidepressant depends on the side effects and the patient’s ability to tolerate the medication. The dose is usually half of that used in the management of depression. Pain is one of the most frequent complaints of patients seen in a medical setting. Thus, the relief of pain is one of the physician’s primary tasks. In most patients, the healing process and/or successful intervention leads to a quick resolution of the pain complaint. Sometimes, however, pain continues despite treatment or apparent healing. In most of these patients, no clearly identifiable cause for the pain can be found.
Over time, the affective and behavioral responses to chronic pain may become prominent and require treatment. One of the most common sequelae of chronic pain is depression.(1) Depression in chronic pain patients may be a normal illness behavior, or it may be a psychopathologic disorder that occurs secondary to chronic pain.(2,3) Psychopathologic disorders in chronic pain may vary from dysthymic disorder to major depression.(4)
Since both depression and behavioral changes are commonly seen in chronic pain patients, antidepressant drugs have been widely used in the management of chronic pain syndromes. Antidepressants are reported to have analgesic properties that are independent of their effect on mood or behavior. Unfortunately, there have been few well-designed, controlled clinical studies evaluating the use of these drugs in chronic pain.
The antidepressants used in the management of chronic pain may be classified into four groups: (1) heterocyclic antidepressants, such as amitriptyline (A mitril, Elavil, Endep, etc.) and imipramine (Janimine, Tipramine, Tofranil, etc.); (2) atypical antidepressants, such as trazodone (Desyrel) and bupropion (Wellbutrin); (3) monoamine oxidase (MAO) inhibitors, such as phenelzine (Nardil), and (4) triazolobenzodiazepines, such as alprazolam (Xanax).
Mechanism of Action
The efficacy of antidepressants in chronic pain may be due to both the antidepressant activity and the direct analgesic activity of these drugs. In patients with pain as part of the symptom complex of depression, the pain generally resolves following resolution of the depression.(5) On the other hand, many antidepressants, especially amitriptyline and doxepin (Adapin, Sinequan), have been reported to relieve pain without significant alleviation of depression.(6) With most antidepressants, the analgesic response usually precedes the antidepressant response by several days, and it occurs at a lower dose.(5)
The direct analgesic effect of antidepressants may be secondary to their effect on the serotoninergic system, which is believed to be one of the primary mechanisms in pain modulation. Animal studies provide further support for the direct analgesic effect of antidepressants.(7)
Antidepressants increase the efficacy of other analgesics, including narcotics.(8) They probably produce this effect by increasing the blood level of narcotics.
The efficacy of antidepressant therapy in chronic pain syndromes depends on both the site and the nature of the pain. Antidepressants, particularly the tricyclics, have been shown to be effective in the management of headache (especially tension headache and migraine), diabetic neuropathy, rheumatoid arthritis, postherpetic neuralgia and atypical facial pain. The role of antidepressants in back pain and pain of mixed etiology is less clear.(9-17)
MAO inhibitors, which are also antidepressants, have been used in the treatment of atypical facial pain and pain as a symptom of depression. Phenelzine, the MAO inhibitor most commonly used, has been effective in managing both of these syndromes.(18,19)
Choice of Drug
The antidepressants most frequently used in clinical studies of chronic pain are doxepin, amitriptyline, imipramine and clomipramine (Anafranil).(9-17) These drugs have more serotoninergic uptake inhibition than the other currently available heterocyclic antidepressants. There is no clear indications that these agents are superior to desipramine (Norpramin, Pertofrane), nortriptyline (Aventyl, Pamelor), trimipramine (Surmontil), amoxapine (Asendin) or trazodone. On a theoretic basis, however, antidepressants that affect the serotoninergic system are considered the drugs of first choice.
The choice of antidepressant depends on the patient’s age, the clinical presentation and the side effect profile of the drug.(20) Thus, the selection of an antidepressant for pain relief is based on the same considerations used in the selection of an antidepressant for the management of depression.
The choice of antidepressant, in terms of side effects, is based on an assessment of the agent’s sedative effects, cardiac conduction effects and anticholinergic activity, as well as its tendency to produce orthostatic hypotension.
Drugs with stronger sedative effects, such as amitriptyline, doxepin, trazodone and trimipramine, are generally useful because insomnia is a common problem in patients with chronic pain. MAO inhibitors are used primarily in the treatment of atypical facial pain. Alprazolam is particularly effective in fibromyalgia.
Fluoxetine (Prozac), a new antidepressant with a potent effect on the serotoninergic system, may be especially useful. We recently administered fluoxetine to 20 patients with chronic low back pain. The drug was well tolerated and produced moderate to marked pain reduction in ten of our patients. The doses ranged from 20 to 80 mg per day, but the usual dose required for pain relief was 20 mg. Nausea and insomnia were common side effects. To reduce the effect of fluoxetine on sleep, the drug should be administered in the morning. Fluoxetine should not be coadministered with 1-tryptophan (Trofan, Tryptacin), which may cause restlessness and nausea and may potentiate the side effects of fluoxetine.
Dose of Antidepressant
In chronic pain patients with no accompanying major depression, it is best to initiate treatment with 25 to 50 mg of a heterocyclic antidepressant one to two hours before bedtime. The dose is then increased by 25 mg every three to four days until a therapeutic response is obtained.(5,11) Patients with chronic pain seem to develop side effect when the daily dose of antidepressant is 75 to 100 mg. Therapeutic dose ranges for various antidepressants used in chronic pain syndromes are given in Table 3.(5)
The analgesic therapeutic response to an antidepressant occurs within the first five days of therapy and continues over the next month.(5,11) Improvement in sleep usually occurs within the first two to three days, except with fluoxetine. Improvement in pain is primarily a reduction in intensity; the character and location of the pain usually remain unchanged. In fibromyalgia and tension headache, the reduction in intensity may be accompanied by a reduction in the number of pain sites.
In patients with a significant psychiatric illness, such as major depression, the starting dose and the dose range are similar to those used in the treatment of primary depression, or approximately twice those used in the management of chronic pain syndromes.(5,11) Lower doses and slow rates of increase are necessary in patients over age 60 and especially in patients with postherpetic neuralgia.
The physician should inform the patient of the expected benefits and possible adverse effects before antidepressant therapy is started. A careful drug history should be taken to identify the patient’s current medications. A complete blood count, an electrocardiogram and liver function tests should be performed, especially in the elderly patient. Trazodone should be tried first in the chronic pain patient with a significant cardiovascular problem, especially a cardiac conduction defect.
Before starting an antidepressant, the patient should be evaluated for open-angle glaucoma and, if elderly, for prostatic problems, both of which are relative contraindications to the administration of tricyclic antidepressants. If the patient has a known prior sensitivity to anticholinergic problems, drugs with the fewest anticholinergic properties, such as trazodone and desipramine, should be tried first. (We have provided more detailed information on the selection of antidepressants in the book Chronic Pain.(5))
Once a clinical response is obtained, most patients require antidepressant therapy for months to years. In patients with pain as a symptom of depression or another self-limiting psychiatric illness, the drug may be tapered and discontinued after about six months to one year.
Special precautions must be taken in the use of MAO inhibitors. Before starting phenelzine therapy, patients should be instructed to follow a tyramine-free diet and to avoid certain medications, such as meperidine (Demerol), sympathomimetic amines and other antidepressants. The usual starting dose of phenelzine is 15 mg per day; this dose is increased by 15 mg every two to three days. In most cases, the dose required for pain relief is 45 to 60 mg a day.(19) When facilities are available, a platelet MAO level should be obtained before phenelzine is started and again after three to four weeks of therapy. Raft and colleagues(19) found that phenelzine was effective in relieving pain as a symptom of depression when platelet MAO levels decreased by at least 80 percent.
Efficacy of Tricyclic Antidepressants in Chronic Pain Syndromes([)
Type of pain Efficacy
Pain in depression + + +
Diabetic neuropathy + + +
Fibromyalgia + + +
Headache + +
Postherpetic neuralgia + +
Arthritis + +
Atypical facial pain + +
Deafferentation pain + +
Psychogenic pain +
Back pain +
Trigeminal neuralgia 0
0 = none; + = minimal; + + = moderate; + + + = strong. ([)–Based on both controlled and uncontrolled studies reviewed in France RD, Krishnan KR. Psychotropic drugs in chronic pain. In: France RD, Krishnan KR, eds. Chronic pain. Washington, D.C.: American Psychiatric Press, 1988:322-74.
Relative Side Effect Profiles of Selected Antidepressant Drugs
Orthostatic Sedative Cardica conduction
Drug hypotension effects effects
Doxepin + + + + + + + + + +
+ + +
Amitriptyline + + + + + + + + + + + +
+ + + +
(Amitril, Elavil, Endep, etc.)
Imipramine + + + + + + + + + +
+ + +
Clomipramine + + + + + + + + + +
Desipramine + + + +
Nortriptyline + + + + + +
Trimipramine + + + + + + + + + +
+ + +
Amoxapine + + + + + + +
Protriptyline + + + + +
+ + +
Trazodone + + + + + +
Maprotiline + + + + + + +
Fluoxetine (Prozac) + 0 +
+ + = weak; + + = mild; + + + = moderate; + + + + = strong.
Antidepressant Drugs: Therapeutic Dose Ranges in Chronic Pain Syndromes
Drug Dose range (mg)
Doxepin (Adapin, Sinequan) 25-100(*)
Amitriptyline (Amitril, Elavil, Endep, etc.) 25-100(*)
Imipramine (Janimine, Tipramine, Tofranil, etc.) 50-100(*)
Desipramine (Norpramin, Pertofrane) 50-75(*)
Nortriptyline (Aventyl, Pamelor) 25-100(*)
Trimipramine (Surmontil) 50-100(+)
Amoxapine (Asendin) 100-200(+)
Protriptyline (Vivactil) No data
Trazodone (Desyrel) 50-200(+)
Maprotiline (Ludiomil) 50-100(+)
Fluoxetine (Prozac) 20
Phenelzine (Nardil) 15-45(*)
Isocarboxazid (Marplan) 10-40(*)
Tranylcypromine (Parnate) 10-20(*)
Alprazolam (Xanax) 0.5-3.0(+)
(*)–Based on controlled clinical studies. (+)–Based on care reports and clinical experience. REFERENCES (1)Hendler N. Depression caused by chronic pain. J Clin Psychiatry 1984;45(3 Pt 2):30-8. (2)Pilowsky I, Spence ND. Illness behaviour syndromes associated with intractable pain. Pain 1976;2:61-71. (3)Krishnan KR, France RD, Houpt JL. Chronic low back pain and depression. Psychosomatics 1985;26:299-302. (4)Krishnan KR, France RD, Pelton S, McCann UD, Davidson J, Urban BJ. Chronic pain and depression. I. Classification of depression in chronic low back pain patients. Pain 1985;22:279-87. (5)France RD, Krishnan KR. Psychotropic drugs in chronic pain. In: France RD, Krishnan KR, eds. Chronic pain. Washington, D.C.: American Psychiatric Press, 1988:322-74. (6)Lance JW, Curran DA. Treatment of chronic tension headache. Lancet 1964;1(7345):1236-9. (7)Spiegel K, Kalb R, Pasternak GW. Analgesic activity of tricyclic antidepressants. Ann Neurol 1983;13:462-5. (8)Malseed RT, Goldstein FJ. Enhancement of morphine analgesia by tricyclic antidepressants. Neuropharmacology 1979;18:827-9. (9)Tyber MA. Treatment of the painful shoulder syndrome with amitriptyline and lithium carbonate. Can Med Assoc J 1974;111:137-40. (10)Turkington RW. Depression masquerading as diabetic neuropathy. JAMA 1980;243:1147-50. (11)France RD, Houpt JL, Ellinwood EH. Therapeutic effects of antidepressants in chronic pain. Gen Hosp Psychiatry 1984;6:55-63. (12)Hameroff SR, Cork RC, Scherer K, et al. Doxepin effects on chronic pain, depression and plasma opioids. J Clin Psychiatry 1982;43(8 Pt 2):22-7. (13)Taub A. Relief of postherpetic neuralgia with psychotropic drugs. J Neurosurg 1973;39:235-9. (14)Jenkins DG, Ebbutt AF, Evans CD. Tofranil in the treatment of low back pain. J Int Med Res 1976;4(2 Suppl):28-40. (15)Blumer D, Heilbronn M. Antidepressant treatment for chronic pain. Treatment outcome of 1,000 patients with the pain prone disorder. Psychiatr Ann 1984;14:796-800. (16)Lindsay PG, Wyckoff M. The depression-pain syndrome and its response to antidepressants. Psychosomatics 1981;22:571-3,576-7. (17)Pilowsky I, Hallett EC, Bassett DL, Thomas PG, Penhall RK. A controlled study of amitriptyline in the treatment of chronic pain. Pain 1982;14:169-79. (18)Lascelles RG. Atypical facial pain and depression. Br J Psychiatry 1966;112:651-9. (19)Raft D, Davidson J, Wasik J, Mattox A. Relationship between response to phenelzine and MAO inhibition in a clinical trial of phenelzine, amitriptyline and placebo. Neuropsychobiology 1981;7:122-6. (20)Baldessarini RJ. Biomedical aspects of depression and its treatment. Washington, D.C.: American Psychiatric Press, 1983.
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