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Therapeutic effects of antidepressants in chronic pain
Therapeutic Effects of Antidepressants in Chronic Pain Randal D. France, M.D. Assistant
Professor,
Department
of Psychiatry,
Duke Medical
Center
Jeffrey L. Houpt, M.D. Professor
and Chairman,
Department
Everett H. Ellinwood, Professor,
Department
of Psychiatry,
of Psychiatry,
Emory School of Medicine
M.D. Duke Medical Center
Abstract: Depression and chronic pain syndromes are often associated. Over the last twenty years there has been a number of controlled and uncontrolled studies evaluating the efficacy of antidepressants in various pain problems. Theadministration of antidepressant medications in the management of chronic pain has become a commonly prescribed therapeutic modality in the treatment of this complex syndrome. This paper reviews the clinical studies in which antidepressants have been used to control chronic pain, summarizes the results of the clinical studies, and comments on the mechanism of action of antidepressants in chronic pain.
The coexistence of pain and depression has been the subject of clinical reports and scientific investigation for several years. So common is the finding, that certain symptoms in depression are almost always part of the chronic pain picture. These include sleep disorder and a decrease in general daily activities and energy [l]. Clinical experience leads to the supposition that there are at least two distinct processes going on. In the one instance there appears to be a group of patients who, in response to the chronic pain disorder, become reactively depressed. A second group appears to be those patients with endogenous depression in which pain represents one of the primary depressive symptoms. Not surprisingly, therefore, psychotropic drugs have become commonly employed in the Gemml Hospital Psychuztry 6, 55-63, 1Y84 C Elsevier Science Publishing Co., Inc. 1984 52 Vanderbilt Avenue, New York, NY 10017
treatment of chronic pain syndromes. Although data are hard to come by concerning the frequency of prescription, our personal experience at the Duke Pain Clinic, and conversations with other professionals suggest that the use of tricyclic antidepressants alone or in combination with an alerting phenothiazine is a common approach to the chronic pain patient. We would estimate that nearly every patient who is referred to our clinic has at least had a trial on one of these drugs. While one might reasonably assume that the popular use of psychotropic drugs argues for evidence of clinical correlation between psychotropic drug and pain relief, one might equally argue for more rigorous definitions and studies of efficacy. This particular paper attempts to set the stage for such a discussion by reviewing the clinical evidence for effectiveness of psychotropic drugs and chronic pain conditions. Because the subject is generally or often dealt with in a rather global fashion of chronic pain vis-a& psychotropic, this paper will depart from that format and deal with discrete pain entities individually. Specifically, we will review the efficacy of antidepressants in patients with pain from arthritis, postherpetic neuralgia, diabetic neuropathy, headaches, facial pain, back pain, and pains of multiple etiologies. Finally, this paper will speculate on certain possible mechanisms of action of these drugs.
55 ISSN 0163-8343/W/$3 00
R. D. France, J. L. Houpt, and E. H. Ellinwood
Review of Clinical Experience Arthritis McDonald Scott [Z] reported on the use of imipramine in twenty-two selected patients having rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis and negative psychiatric histories. In a crossover double-blind trial using 75 mg of imipramine versus a placebo, he found a significant number of patients preferring and physicians rating imipramine over the placebo. In a multicenter study using patients with types of arthritis similar to those reported on by McDonald Scott, Gringras [3] found significant improvement in pain, stiffness, and grip strength in 55 patients using imipramine (75 mg per day) as compared to a placebo in a double-blind crossover study. Patients having signs of clinical depression were excluded. Thus, these studies demonstrated pain relief with a tricyclic antidepressant in the absence of depression. Haydu et al. [4] showed a decrease in the rheumatoid factor in nonarthritic psychotic patients using imipramine. However, in a double-blind trial using imipramine (75 mg per day), McNeil [5] failed to show a change in the level of the rheumatoid factor in 20 patients who had rheumatoid arthritis and were free of psychiatric illness. In a preliminary report, Regalando [6] has suggested the addition of a small dose of clomipramine to the conventional analgesic therapy of patients with chronic joint pain to modify the pain threshold and reduce the dose of analgesics. The pilot study [7] conducted on 41 patients with joint pain showed that 57% of patients felt better when clomipramine at a dose of either 10 mg or 25 mg per day was added to their standard analgesic regime. No difference in effectiveness was observed at either the 10 mg or 25 mg dose. Ganvir [8] examined 49 patients suffering from joint pain, using either 25 mg per day of clomipramine or a placebo in a double-blind study. He found no difference in pain rating in each group. Tyber 191 treated 56 patients exhibiting monoarticular shoulder pain with lithium and amitriptyline (75 mg per day). Seventy-six percent of this sample had clinical evidence of depression and one-third had increased calcification of the shoulder joint confirmed by radiologic examination. Forty-four patients showed a marked clinical improvement with a disappearance or a decrease in the calcium deposit on radiologic reexamination after treatment.
56
Postherpetic Neuralgia In 1965, Woodforde et al. [lo] demonstrated a decrease in pain in 11 out of 14 patients suffering from postherpetic neuralgia treated with 100 mg per day of amitriptyline. All 14 of their patients complained of depressive symptoms. Taub [ll] reported that five patients with postherpetic neuralgia experienced complete relief of pain within l-2 weeks of treatment with a combination of amitriptyline in a dose range of 50-100 mg per day and a phenothiazine. Three of five patients showed no response to the tricyclic alone, leading to the preliminary suggestion that a combination of a tricyclic antidepressant plus a phenothiazine is necessary to decrease the pain in postherpetic neuralgia. Hatangdi 1121reported on 34 patients with postherpetic neuralgia treated in a pain clinic for three years. Medical management included antiepileptic agents (carbamazepine or diphenylhydantoin) and nortriptyline (So-100 mg per day). Seventy-nine percent (27 out of 34) obtained substantial pain relief. The beneficial effects of treatment (improvement in sleep) were seen in the first several days of treatment, and pain quickly reappeared upon discontinuation of the medication. Watson et al. [13], in a randomly assigned, double-blind crossover study using amitriptyline or placebo, studied the effects in 24 patients with postherpetic neuralgia. Sixteen out of 24 patients (66%) had significant pain relief in the drug period, and one out of 24 experienced satisfactory pain relief in the placebo period. Throughout this study, depression was assessed by self-rating instruments. There was no correlation between pain relief and change in depression scores, illustrating pain relief from amitriptyline with no antidepressant effect from the drug.
Diabetic Neuropathy Davis et al. [14] first reported the successful use of amitriptyline with fluphenazine in eight patients having burning dysesthesias of diabetic neuropathy. Turkington [15] studied 59 patients exhibiting painful diabetic neuropathy. The patients were found to be clinically depressed. Using a doubleblind protocol, patients were equally divided into three patient groups based on drug treatment: 1) amitriptyline, 2) imipramine, and 3) diazepam. The dose of both the tricyclic antidepressants were 100 mg per day, and diazepam was dispensed at 15 mg per day. Patients treated with either of the tricyclics
Antidepressants/Chronic Pain
reported complete relief of pain, but patients treated with diazepam showed no improvement. The relief of pain paralleled a lessening of depressive symptoms. The author concluded that the leg pains are a manifestation of depression rather than that of diabetes mellitus.
Headaches Antidepressant medications have been suggested for the treatment of migraine [16,17] and chronic tension headaches [ 18,191. Couch [20] evaluated amitriptyline in 110 patients with migraine. In this open study, he showed that amitriptyline reduced the frequency of the headache by 50% in 72% of the patients. Twenty percent of the group were rated as depressed. There was a weak relationship between improvement in depression and migraine. Noone [21] demonstrated that 30 mg of clomipramine per day was effective in reducing the duration and frequency of migraine headaches in eight patients. Gomersall and Stuart [22] in a double-blind controlled study of crossover design demonstrated that 16 out of 20 subjects had fewer migraine attacks when treated with amitriptyline (dose range of 10-60 mg per day) as compared to the placebo. The patients showed no signs of clinical depression. Amitriptyline had its greatest effect on attacks without a specific precipitating cause, and its least effect on attacks brought about by fatigue. In a doubleblind trial, Couch [23] evaluated the effects of amitriptyline (100 mg per day) versus the placebo in 100 migraine patients. He found amitriptyline significantly more effective than the placebo in reducing both the frequency and duration of the headaches. In nondepressed patients with severe migraine and depressed patients exhibiting less severe migraine, amitriptyline was most effective, but it was less able to give relief in depressed patients with severe migraine. Couch also observed that the prophylactic effects of the drug occurred within the first month of treatment and independent of its mood-elevating activity. Sherwin [24] had a positive response in 10 out of 14 patients with chronic tension headaches, using amitriptyline (100-200 mg per day) and perphenazine (8-64 mg per day). There was a direct correlation between decrease in headaches and depression rating scores. In a double-blind study, Diamond et al. [25] examined the effects of amitriptyline in 56 patients with chronic tension head-
aches. He divided the patients into three treatment groups: those receiving 10 and 25 mg per day of amitriptyline, respectively, and those receiving the placebo. Amitriptyline at either dose produced a significant difference in pain relief as compared to the placebo. However, there was no difference observed between the groups receiving either the 10 mg or 25 mg of amitriptyline. Lance and Curran [18] compared the effects of nine active drugs with the placebo in 280 patients having chronic tension headaches. Patients treated with amitriptyline (30-75 mg per day) showed a significant improvement in the relief of headaches as compared to those treated with placebo. When compared to other active treatments, amitriptyline was more effective than diazepam, chlordiazepoxide, bellergal, and methysergide. The majority of patients showed no indications of depression. Further, it appeared that patients who had some degree of depression were not “influenced selectively” by use of amitriptyline. Holt [26], in a review of Lance and Curran’s article, criticized these statistical comparisons and suggested that the “relative effectiveness of the drugs” is unclear. In a simpler design study, Okasha [27] compared the efficacy of doxepin (30-50 mg per day), amitriptyline (30-50 mg per day), diazepam (6-10 mg per day), and the placebo in a double-blind trial involving 80 patients with psychogenic headaches. Assessment of depression and anxiety was made by the use of Hamilton Rating Scales. In the first month of therapy, doxepin and amitriptyline were more effective than diazepam in relieving headaches. All three active drugs were superior to the placebo. After two months, only doxepin was significant in the relief of headaches and the diminishment of depression and anxiety.
Facial Pain Gessel[28]
treated a group of 23 patients with myofascial pain-dysfunction symptoms of the face with biofeedback. Fifteen out of 23 patients improved, and four out of the remaining eight who did not improve with biofeedback had a positive response to 100 mg per day of amitriptyline. Lascelles [29] treated 40 patients having facial pain caused by mixed etiologies with phenelzine (45 mg per day) for one month in a double-blind fashion crossing over the placebo. Changes in depressive symptoms were assessed by the Hamilton
57
R. D. France, J. L. Houpt, and E. H. Ellinwood Depression Rating Scale. Improvement in both depression and facial pain was significant with phenelzine, as compared to the placebo.
Back Pain Jenkins et al. 1301compared imipramine (75 mg per day) and a placebo in 44 patients with low back pain who had been admitted to a rehabilitation unit. Using a double-blind design they found no statistical difference between the two groups in assessments of pain, stiffness, straight leg raise, backward flexion, and depression by self-rating instruments. By contrast, in a double-blind study, Hameroff et al. [31] examined 30 patients with chronic low back pain and cervical pain with coexisting depression and found that the group treated with doxepin (2.5 mg per kg) improved significantly, as compared to the placebo group. Improvement was observed in the lessening of pain, depression, muscle tension, insomnia, and mood.
Chronic Pain: Mixed Etiologies Since the first report by Paoli 1321where imipramine promoted pain relief in a number of clinical states, various authors [33-351 have presented case studies involving the effectiveness of antidepressants in chronic pain due to neurologic and musculoskeletal disorders. Merskey and Hester [36] reported on 28 out of 30 patients with chronic pain caused by lesions of the nervous system, who responded to a combination of tricyclic antidepressants and phenothiazines. The authors felt that the effects were secondary to the direct analgesic action of the drugs on the central nervous systems since only one of the patients showed evidence of primary depression while the remaining patients had depression secondary to their pain problem. Kocher [37] published the results of 103 patients with chronic pain produced by neurologic conditions treated with a combination of antidepressants and phenothiazines. Eighty-two percent of the patients showed a marked improvement. Clarke [38] treated chronic pain patients with amitriptyline (75 mg) and perphenazine (2 mg). After two months, 68% of the patients were pain free. The best results were in patients with postherpetic neuralgia and postoperative scar pain. Carasso et al. [39] evaluated the effects of two serotonergic reuptake blockers (clomipramine and amitriptyline) involving 67 pain
patients with chronic neurologic disease. It is suggested from this single-blind study that clomipramine (20-75 mg per day) was more effective in trigeminal neuralgia and tension headaches, whereas amitriptyline (30-110 mg per day) is better in treating postherpetic neuralgia. In twenty-two hospitalized elderly patients with chronic illness, Evans et al. [40] failed to demonstrate any difference on pain control in depression in a double-blind comparison between doxepin (150 mg per day) and a placebo. Johansson and von Knorring [41] studied 40 patients with pain syndromes due both to organic and psychogenic origins. They conducted a double-blind controlled study using zimelidine (a serotonic uptake inhibitor) versus a placebo. The zimelidine group experienced significant greater pain relief and reduced usage of analgesics in comparison to the placebo group. The pain relief occurred independently of changes in the depression rating. Singh and Verma [42] treated 60 patients presenting with pain as the primary complaint in the absence of physical findings, to a psychiatric outpatient clinic using chlordiazepoxide, amitriptyline, or imipramine. Thse patients treated with either of the tricyclic antidepressants experienced significantly greater improvement than those medicated with chlordiazepoxide. Ward et al. [43] demonstrated the effectiveness of doxepin in reducing chronic pain in patients diagnosed as having a clinical depression. There was a significant relationship between the improvement of depression and the relief of pain. Bradley [44] divided 35 patients into two groups characterized by 1) the onset of pain prior to depressive symptoms, or 2) the onset of pain and depression simultaneously. When the patients were treated for depression, he found, in the first group, that the depression alone responded to treatment, and in the second group, both pain and depression were relieved simultaneously. However, Lindsay and Wychoff [45] demonstrated that 96 of 116 patients (83%) obtained significant pain relief associated with the antidepressant drug irrespective of the onset of pain and depression. In a double-blind crossover study, Pilowsky et al. [46] failed to demonstrate a reduction in pain in 32 patients using amitriptyline, as compared to a placebo. These patients were referred to a multidisciplinary pain clinic for the management of chronic pain where no organic cause of the pain could be detected.
Antidepressants/Chronic Pain
Discussion The most frequent antidepressants used in the following review are the ones that have significant serotonic uptake inhibition (doxepin, amitriptyline, clomipramine, and imipramine). This is congruent with the experimental evidence showing central nervous system serotonergic neurons involved in nociception [47]. Pain from chronic conditions such as migraine appear to be under tonic inhibition by pathways involving a serotonergic link. For example, plasma serotonic drops before the precipitation of migraine episodes [48], and parachlorophenylalanine, a serotonic synthesis inhibitor, triggers pain in migraine patients but not in controls [49]. Recent evidence, as summarized by Basbaum and Fields [50,51] provides a picture of a pain-activated inhibitory feedback circuit from the para-aqueductal gray area via the serotonergic raphe nucleus, which projects to primary pain sensory input areas such as lamina I and V of the spinal dorsal horn and the trigeminal caudalis. The pain-modulating pathways involve enkephalins and serotonin, as well as [51]. The noradrenergic neurotransmitters serotonergic pathways from the raphe appear to be at least partially in series with enkephalin, since naloxone can block raphe-induced analgesia [52]. Opiate analgesia is inhibited by serotonic depletion with neurotoxins [53], parachlorophenylalanine [54], or electrolytic lesions of the raphe [55,56]. Johansson 1571 found a positive correlation between levels of endorphins and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid of chronic pain patients. When these patients were treated with zimelidine, patients had significant relief of pain and reduction in levels of endorphins and 5HIAA, while no significant changes occurred with the placebo. In the studies [15,18,27,39,42,45] comparing the relative effectiveness of one antidepressant versus another, there is no single antidepressant that is more effective than the others for chronic pain states. There are some authors advocating the use of antidepressants in combination with phenothiazines [11,14,24,36-381, antiepileptic drugs [12], or lithium [9]. Unfortunately, these are case report studies and the effectiveness of antidepressants alone or in combination with other psychoactive drugs cannot be determined. The dose range of antidepressants most frequently reported in these studies is approximately of 50-100 mg per day. Except for clinical experi-
ence, it is unclear why this dose range, which is lower than that seen in primary depression, appears to be effective in chronic pain states. Only four studies [13,31,43,46] reported blood levels of tricyclic antidepressants. Using amitriptyline, Watson et al. [13] showed a decrease in pain levels in patients suffering from postherpetic neuralgia, with the mean plasma level of amitriptyline at 67 ng/ml and for nortriptyline at 38 ng/ml. The mean combined plasma level of amitriptyline and nortriptyline (105 ng/ml) is below the therapeutic ranges known for antidepressant effects. Hammeroff et al. (311 demonstrated improvement in depression and pain in patients with back pain, when the combined plasma level of doxepin and its metabolite desmethyldoxepin reached 70 ng/ml, below the therapeutic levels for endogenous depression. The lower dose range observed in clinical trials, and reports of lower therapeutic plasma thresholds of antidepressants seen in chronic pain-as compared to primary depression-may indicate that antidepressants work by a mechanism other than their mood-elevating activity in chronic pain states. In this review (see Table l), antidepressants used in 12 out of 16 clinical trials utilized in double-blind controlled studies with a placebo [5,8,23,27,30,31, 40,41,57] or crossover design [2,3,13,18,22,29,46] gave a greater than 55% improvement in the treatment of chronic pain. Four studies [8,30,40,46] showed equivocal results. Four out of four studies [ lO,ll, 19,421 employing consecutive-cases design showed a significant improvement with antidepressants in chronic pain. Nine studies [5,9,10,15, 24,27,29,31,44] have shown a direct correlation between an improvement in depression and chronic pain. However, five studies [13,18,20,23,41] have demonstrated pain relief without a parallel effect on depression. In three studies [2,3,22], when the authors excluded chronic pain patients with clinical evidence of depression, pain relief was obtained using antidepressants. Antidepressants were significantly effective in depressed patients with pain complaints in two studies [11,42]. Despite the frequent use of antidepressants in chronic pain, their mechanism of action is unknown. There are two major hypotheses regarding the therapeutic nature of antidepressants in chronic pain: 1) theory of direct or potentiated analgesic effects, and 2) theory of mood-activating property. In support of the direct analgesic theory, it is clinically observed that the effects of antidepressants in chronic pain are seen at lower dose ranges
59
Table 1 Improvement + Clinical state Author of study
Controlled study
Arthritis McDonald Scott (2) Gringras (3) Tyler (9)
Type of iv
dr% imipramine imipramine amitriptyline lithium lomipramine clomipramine
Yes Yes no
22 55 56
no Yes
41 49
no no
14 5
Hatangdi (12)
no
34
Watson (13) Diabetic neuropathy Davis (14)
Yes
22
no
8
Turkington (15)
Yes
59
Yes Yes Yes
16 100 280
Okasha (27)
Yes
80
Couch (20) Noone (21) Diamond (25) Sherwin (24)
no no Yes no
110 8 56 14
Facial pain Lascelles (29) Back pain
Yes
40
phenelzine
Jenkins (30) Hameroff (31)
Yes Yes
44 27
imipramine doxepin
no
28
various TCA’s
Regalando (7) Ganvir (8) Postherpetic neuralgia Woodforde (10) Taube (11)
Headaches Gomersall & Stuart (22) Couch (23) Curran and Lance (18)
Mixed etiologies Merskey (36) Kocher (37)
no
103
Carasso (39)
no
67
Evans (40) Johanssen (41) Pilowsky (46) Clarke (38)
Yes Yes Yes no
22 32 32
120
Dose (mg)
amitriptyline amitriptyline phenothiazine nortriptyline antiepileptics amitriptyline amitriptyline phenothiazine amitriptyline imipramine diazepam amitriptyline amitriptyline amitriptyline imipramine other drugs doxepin amitriptyline diazepam amitriptyline clomipramine amitriptyline amitriptyline perphenazine
phenothiazone various TCA’s phenothiazine clomipramine amitriptyline doxepin zimelidine amitriptyline amitriptyline perphenazine
Presence 0P depression
75 75 75
b b
Pain
Depression
C
60* 52* 79
? ? +
lo-25 25
a a
57 0
? ?
100 25-100
C C
79 100
+ ?
50-100
a
79
?
75
C
66*
-
100
?
100 100 15
C
100
+
lo-60 100 30-75 30-75
b
80* 55.3* 55*
-
30-50 30-150 6-10 75 30 lo-25 100-200 8-64
C
P
+
C
72 100
45 75 2.5 mg/kg
20-75 30-100 150 200 150 75 2
C C
a C C
P 70
? ? +
75*
+
0
0 +
C
93
?
a
92
?
a
54
?
0
0 -
C
C C
P
! 68
0 ?
*a, depression not examined; b, depressed patients excluded; c, depression diagnosed or rated. + results are statistically significant; p, mean scores (prey and post-test changes are statistically significant; 0, no difference pre- and post-test; ?, not reported; -, no correlation between improvements in pain and depression scores; +, direct relationship behveen improvement
60
in pain and depression
scores.
Antidepressants/Chronic Pain
and have more rapid onset of action than the response of antidepressants in depression [30]. Although the dose range of tricyclics in chronic pain patients is usually one-half that used to treat depression, the effects of tricyclics in chronic pain are seen in the first week of treatment, while effects on depression are usually delayed 3-4 weeks. Tricyclic antidepressants are thought to work by increasing levels of norepinephrine and serotonic by blocking their uptake by the presynaptic neurons. These neurotransmitters, especially serotonin, are involved in the descending spinal cord pathways, which inhibit pain transmission [51]. Hence, the tricyclic antidepressants may act directly on pain pathways. In addition, Couch [20,23] and Lance and Curran [18] have reported pain relief with tricyclics in chronic pain patients free of depression. Johansson [57] has shown pain alleviation without changes in depression ratings in patients with chronic pain treated with an antidepressant. For some time, it has been accepted that chronic pain patients often suffer from depression. Sternbath [58] has demonstrated high evidence of depression on MMPI’s in chronic pain patients. Merskey ]59] has diagnosed a high degree of secondary depression in patients with pain, and most recently Blumer [60] has theorized chronic pain as being a variant of depression. The beneficial effects of antidepressants as a result of their mood-elevating characteristics is evident in a number of studies showing a positive correlation between improvement in depression and pain relief [5,10,15,29]. In addition, Bradly [44] has shown that when pain begins with the onset of depression both can be relieved with treatment of the depression.
Summary Antidepressants are commonly used to treat chronic pain irregardless of etiology since the first report by Paoli [32] twenty-two years ago. However, there have been few controlled studies evaluating the efficacy of antidepressants in chronic pain. From the review, it is apparent that additional randomized controlled studies utilizing either doubleblind placebo or various methods should be done. This is important since the placebo response rate with tricyclics in depression is 47% [61]. To address the question of which neurotransmitter systems are important in pain inhibition, studies comparing the efficiency of norepinephrine reup-
take blocker (desipramine) versus serotonic reuptake blockers should be undertaken. Since there are overlaps in the clinical symptoms and treatment aspects of chronic pain and depression, any treatment outcome studies should control for and rate the type and degree of depression using reliable measures.
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57.
58. 59.
sus placebo in chronic pain patients. Pam 7:69-78, 1979 Singh G, Verma HC: Drug treatment of chronic intractable pain in patients referred to psychiatry clinic J Indian M A 56341-345, 1971 Ward GN, Bloom VL, Friedel RO: The effectiveness of tricyclic antidepressants in the treatment of coexisting pain and depression. Pain 2331-341, 1979 Bradley JJ: Severe localized pain associated with the depressive syndrome. Br J Psychiatry 109:741-745, 1963 Lindsay PG, Wyckoff M: The depression-pain syndrome and its response to antidepressants. Psychosomatics 22:571-577, 1981 Pilowsky I, Hallett EC, Bassett DL, Thomas PG, Penhall RK: A controlled study of amitriptyline in the treatment of chronic pain. Pain 14:169-179, 1982 Messing RB, Lytle LD: Serotonin containing neurons: Their possible role in pain and analgesia. Pain 4:1-21, 1977 Curran DA, Hinterberger H, Lance JW: Total plasma serotonin, 5-hydroxyindoleacetic acid and p-hydroxy-n-methylmandelic acid excretion in normal and migrainous subjects. Brain 88:997-1010, 1965 Sicuteri F, Anselmi B, Fanciullacci M: The serotonin (5-HT) theory of migraine. Adv Neurol 4:383-394, 1974 Basbaum A, Fields HL: Endogenous pain control mechanisms: Review and hypothesis. Ann Neurol 4:451-462, 1978 Basbaum AI, Fields HL: Pain control: A new role for the medullary reticular formation. In Hobson JA and Brazier MAB (eds). The Reticular Formation Revisited. New York, Raven Press, 1980 Oliveras JL, Hosobuchi Y, Redjemi F et al: Opiate antagonist, naloxone, strongly reduces analgesia induced by stimulation of a raphe nucleus (centralis inferior). Brain Res 120221-229, 1977 Vogt M: The effect of lowering the 5-hydroxytryptamine content of the rat spinal cord on analgesia produced by morphine. J Physiol (Lond) 236:483498, 1974 Tenen SS: Antagonism of the analgesic effect of morphine and other drugs by p-chlorophenylalanine, a serotonin depletor. Psychopharmacologia 12:278285, 1968 Proudfit HK, Anderson EC: Morphine analgesia: Blockade by raphe magnus lesions. Brain Res 98:612618, 1975 Yaksh TL, DuChateau JC, Rudy TA: Antagonism to methysergide and cinanserin of the antinociceptive activity of morphine administered into the periaqueductal gray area. Brain Res 104:367-372, 1976 Johansson F, Knorring LV, Sedvall G, Terenius L: Changes in endorphins and 5-hydroxyindoleacetic acid in cerebrospinal fluid as a result of treatment with a serotonin reuptake inhibitor (zimelidine) in chronic pain patients. Psychiatry Res 2:167-172,198O Sternbach RA: Pain. A Psychophysiological Analysis. New York, Academic Press, 1968 Merskey H, Spear FG: Pain, psychological and psychiatric aspects. London, Bailliere, Tindall and Cassel, 1967
Antidepressants/Chronic
60. Blumer D, Heilb M: Chronic pain as a variant of depressive disease the pain-prone disorder. J Nerv Mental Dis 170:381-394, 1982 61. Klaman GL, Cole JO: Clinical pharmacology of imipramine and related antidepressant compounds. Pharmacol Rev 17:101, 1965
Pain
Direct reprint request to: Randal D. France, M.D. Department of Psychiatry Box 3903 Duke Medical Center Durham, North Carolina 27710
63
Professor,
Department
of Psychiatry,
Duke Medical
Center
Jeffrey L. Houpt, M.D. Professor
and Chairman,
Department
Everett H. Ellinwood, Professor,
Department
of Psychiatry,
of Psychiatry,
Emory School of Medicine
M.D. Duke Medical Center
Abstract: Depression and chronic pain syndromes are often associated. Over the last twenty years there has been a number of controlled and uncontrolled studies evaluating the efficacy of antidepressants in various pain problems. Theadministration of antidepressant medications in the management of chronic pain has become a commonly prescribed therapeutic modality in the treatment of this complex syndrome. This paper reviews the clinical studies in which antidepressants have been used to control chronic pain, summarizes the results of the clinical studies, and comments on the mechanism of action of antidepressants in chronic pain.
The coexistence of pain and depression has been the subject of clinical reports and scientific investigation for several years. So common is the finding, that certain symptoms in depression are almost always part of the chronic pain picture. These include sleep disorder and a decrease in general daily activities and energy [l]. Clinical experience leads to the supposition that there are at least two distinct processes going on. In the one instance there appears to be a group of patients who, in response to the chronic pain disorder, become reactively depressed. A second group appears to be those patients with endogenous depression in which pain represents one of the primary depressive symptoms. Not surprisingly, therefore, psychotropic drugs have become commonly employed in the Gemml Hospital Psychuztry 6, 55-63, 1Y84 C Elsevier Science Publishing Co., Inc. 1984 52 Vanderbilt Avenue, New York, NY 10017
treatment of chronic pain syndromes. Although data are hard to come by concerning the frequency of prescription, our personal experience at the Duke Pain Clinic, and conversations with other professionals suggest that the use of tricyclic antidepressants alone or in combination with an alerting phenothiazine is a common approach to the chronic pain patient. We would estimate that nearly every patient who is referred to our clinic has at least had a trial on one of these drugs. While one might reasonably assume that the popular use of psychotropic drugs argues for evidence of clinical correlation between psychotropic drug and pain relief, one might equally argue for more rigorous definitions and studies of efficacy. This particular paper attempts to set the stage for such a discussion by reviewing the clinical evidence for effectiveness of psychotropic drugs and chronic pain conditions. Because the subject is generally or often dealt with in a rather global fashion of chronic pain vis-a& psychotropic, this paper will depart from that format and deal with discrete pain entities individually. Specifically, we will review the efficacy of antidepressants in patients with pain from arthritis, postherpetic neuralgia, diabetic neuropathy, headaches, facial pain, back pain, and pains of multiple etiologies. Finally, this paper will speculate on certain possible mechanisms of action of these drugs.
55 ISSN 0163-8343/W/$3 00
R. D. France, J. L. Houpt, and E. H. Ellinwood
Review of Clinical Experience Arthritis McDonald Scott [Z] reported on the use of imipramine in twenty-two selected patients having rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis and negative psychiatric histories. In a crossover double-blind trial using 75 mg of imipramine versus a placebo, he found a significant number of patients preferring and physicians rating imipramine over the placebo. In a multicenter study using patients with types of arthritis similar to those reported on by McDonald Scott, Gringras [3] found significant improvement in pain, stiffness, and grip strength in 55 patients using imipramine (75 mg per day) as compared to a placebo in a double-blind crossover study. Patients having signs of clinical depression were excluded. Thus, these studies demonstrated pain relief with a tricyclic antidepressant in the absence of depression. Haydu et al. [4] showed a decrease in the rheumatoid factor in nonarthritic psychotic patients using imipramine. However, in a double-blind trial using imipramine (75 mg per day), McNeil [5] failed to show a change in the level of the rheumatoid factor in 20 patients who had rheumatoid arthritis and were free of psychiatric illness. In a preliminary report, Regalando [6] has suggested the addition of a small dose of clomipramine to the conventional analgesic therapy of patients with chronic joint pain to modify the pain threshold and reduce the dose of analgesics. The pilot study [7] conducted on 41 patients with joint pain showed that 57% of patients felt better when clomipramine at a dose of either 10 mg or 25 mg per day was added to their standard analgesic regime. No difference in effectiveness was observed at either the 10 mg or 25 mg dose. Ganvir [8] examined 49 patients suffering from joint pain, using either 25 mg per day of clomipramine or a placebo in a double-blind study. He found no difference in pain rating in each group. Tyber 191 treated 56 patients exhibiting monoarticular shoulder pain with lithium and amitriptyline (75 mg per day). Seventy-six percent of this sample had clinical evidence of depression and one-third had increased calcification of the shoulder joint confirmed by radiologic examination. Forty-four patients showed a marked clinical improvement with a disappearance or a decrease in the calcium deposit on radiologic reexamination after treatment.
56
Postherpetic Neuralgia In 1965, Woodforde et al. [lo] demonstrated a decrease in pain in 11 out of 14 patients suffering from postherpetic neuralgia treated with 100 mg per day of amitriptyline. All 14 of their patients complained of depressive symptoms. Taub [ll] reported that five patients with postherpetic neuralgia experienced complete relief of pain within l-2 weeks of treatment with a combination of amitriptyline in a dose range of 50-100 mg per day and a phenothiazine. Three of five patients showed no response to the tricyclic alone, leading to the preliminary suggestion that a combination of a tricyclic antidepressant plus a phenothiazine is necessary to decrease the pain in postherpetic neuralgia. Hatangdi 1121reported on 34 patients with postherpetic neuralgia treated in a pain clinic for three years. Medical management included antiepileptic agents (carbamazepine or diphenylhydantoin) and nortriptyline (So-100 mg per day). Seventy-nine percent (27 out of 34) obtained substantial pain relief. The beneficial effects of treatment (improvement in sleep) were seen in the first several days of treatment, and pain quickly reappeared upon discontinuation of the medication. Watson et al. [13], in a randomly assigned, double-blind crossover study using amitriptyline or placebo, studied the effects in 24 patients with postherpetic neuralgia. Sixteen out of 24 patients (66%) had significant pain relief in the drug period, and one out of 24 experienced satisfactory pain relief in the placebo period. Throughout this study, depression was assessed by self-rating instruments. There was no correlation between pain relief and change in depression scores, illustrating pain relief from amitriptyline with no antidepressant effect from the drug.
Diabetic Neuropathy Davis et al. [14] first reported the successful use of amitriptyline with fluphenazine in eight patients having burning dysesthesias of diabetic neuropathy. Turkington [15] studied 59 patients exhibiting painful diabetic neuropathy. The patients were found to be clinically depressed. Using a doubleblind protocol, patients were equally divided into three patient groups based on drug treatment: 1) amitriptyline, 2) imipramine, and 3) diazepam. The dose of both the tricyclic antidepressants were 100 mg per day, and diazepam was dispensed at 15 mg per day. Patients treated with either of the tricyclics
Antidepressants/Chronic Pain
reported complete relief of pain, but patients treated with diazepam showed no improvement. The relief of pain paralleled a lessening of depressive symptoms. The author concluded that the leg pains are a manifestation of depression rather than that of diabetes mellitus.
Headaches Antidepressant medications have been suggested for the treatment of migraine [16,17] and chronic tension headaches [ 18,191. Couch [20] evaluated amitriptyline in 110 patients with migraine. In this open study, he showed that amitriptyline reduced the frequency of the headache by 50% in 72% of the patients. Twenty percent of the group were rated as depressed. There was a weak relationship between improvement in depression and migraine. Noone [21] demonstrated that 30 mg of clomipramine per day was effective in reducing the duration and frequency of migraine headaches in eight patients. Gomersall and Stuart [22] in a double-blind controlled study of crossover design demonstrated that 16 out of 20 subjects had fewer migraine attacks when treated with amitriptyline (dose range of 10-60 mg per day) as compared to the placebo. The patients showed no signs of clinical depression. Amitriptyline had its greatest effect on attacks without a specific precipitating cause, and its least effect on attacks brought about by fatigue. In a doubleblind trial, Couch [23] evaluated the effects of amitriptyline (100 mg per day) versus the placebo in 100 migraine patients. He found amitriptyline significantly more effective than the placebo in reducing both the frequency and duration of the headaches. In nondepressed patients with severe migraine and depressed patients exhibiting less severe migraine, amitriptyline was most effective, but it was less able to give relief in depressed patients with severe migraine. Couch also observed that the prophylactic effects of the drug occurred within the first month of treatment and independent of its mood-elevating activity. Sherwin [24] had a positive response in 10 out of 14 patients with chronic tension headaches, using amitriptyline (100-200 mg per day) and perphenazine (8-64 mg per day). There was a direct correlation between decrease in headaches and depression rating scores. In a double-blind study, Diamond et al. [25] examined the effects of amitriptyline in 56 patients with chronic tension head-
aches. He divided the patients into three treatment groups: those receiving 10 and 25 mg per day of amitriptyline, respectively, and those receiving the placebo. Amitriptyline at either dose produced a significant difference in pain relief as compared to the placebo. However, there was no difference observed between the groups receiving either the 10 mg or 25 mg of amitriptyline. Lance and Curran [18] compared the effects of nine active drugs with the placebo in 280 patients having chronic tension headaches. Patients treated with amitriptyline (30-75 mg per day) showed a significant improvement in the relief of headaches as compared to those treated with placebo. When compared to other active treatments, amitriptyline was more effective than diazepam, chlordiazepoxide, bellergal, and methysergide. The majority of patients showed no indications of depression. Further, it appeared that patients who had some degree of depression were not “influenced selectively” by use of amitriptyline. Holt [26], in a review of Lance and Curran’s article, criticized these statistical comparisons and suggested that the “relative effectiveness of the drugs” is unclear. In a simpler design study, Okasha [27] compared the efficacy of doxepin (30-50 mg per day), amitriptyline (30-50 mg per day), diazepam (6-10 mg per day), and the placebo in a double-blind trial involving 80 patients with psychogenic headaches. Assessment of depression and anxiety was made by the use of Hamilton Rating Scales. In the first month of therapy, doxepin and amitriptyline were more effective than diazepam in relieving headaches. All three active drugs were superior to the placebo. After two months, only doxepin was significant in the relief of headaches and the diminishment of depression and anxiety.
Facial Pain Gessel[28]
treated a group of 23 patients with myofascial pain-dysfunction symptoms of the face with biofeedback. Fifteen out of 23 patients improved, and four out of the remaining eight who did not improve with biofeedback had a positive response to 100 mg per day of amitriptyline. Lascelles [29] treated 40 patients having facial pain caused by mixed etiologies with phenelzine (45 mg per day) for one month in a double-blind fashion crossing over the placebo. Changes in depressive symptoms were assessed by the Hamilton
57
R. D. France, J. L. Houpt, and E. H. Ellinwood Depression Rating Scale. Improvement in both depression and facial pain was significant with phenelzine, as compared to the placebo.
Back Pain Jenkins et al. 1301compared imipramine (75 mg per day) and a placebo in 44 patients with low back pain who had been admitted to a rehabilitation unit. Using a double-blind design they found no statistical difference between the two groups in assessments of pain, stiffness, straight leg raise, backward flexion, and depression by self-rating instruments. By contrast, in a double-blind study, Hameroff et al. [31] examined 30 patients with chronic low back pain and cervical pain with coexisting depression and found that the group treated with doxepin (2.5 mg per kg) improved significantly, as compared to the placebo group. Improvement was observed in the lessening of pain, depression, muscle tension, insomnia, and mood.
Chronic Pain: Mixed Etiologies Since the first report by Paoli 1321where imipramine promoted pain relief in a number of clinical states, various authors [33-351 have presented case studies involving the effectiveness of antidepressants in chronic pain due to neurologic and musculoskeletal disorders. Merskey and Hester [36] reported on 28 out of 30 patients with chronic pain caused by lesions of the nervous system, who responded to a combination of tricyclic antidepressants and phenothiazines. The authors felt that the effects were secondary to the direct analgesic action of the drugs on the central nervous systems since only one of the patients showed evidence of primary depression while the remaining patients had depression secondary to their pain problem. Kocher [37] published the results of 103 patients with chronic pain produced by neurologic conditions treated with a combination of antidepressants and phenothiazines. Eighty-two percent of the patients showed a marked improvement. Clarke [38] treated chronic pain patients with amitriptyline (75 mg) and perphenazine (2 mg). After two months, 68% of the patients were pain free. The best results were in patients with postherpetic neuralgia and postoperative scar pain. Carasso et al. [39] evaluated the effects of two serotonergic reuptake blockers (clomipramine and amitriptyline) involving 67 pain
patients with chronic neurologic disease. It is suggested from this single-blind study that clomipramine (20-75 mg per day) was more effective in trigeminal neuralgia and tension headaches, whereas amitriptyline (30-110 mg per day) is better in treating postherpetic neuralgia. In twenty-two hospitalized elderly patients with chronic illness, Evans et al. [40] failed to demonstrate any difference on pain control in depression in a double-blind comparison between doxepin (150 mg per day) and a placebo. Johansson and von Knorring [41] studied 40 patients with pain syndromes due both to organic and psychogenic origins. They conducted a double-blind controlled study using zimelidine (a serotonic uptake inhibitor) versus a placebo. The zimelidine group experienced significant greater pain relief and reduced usage of analgesics in comparison to the placebo group. The pain relief occurred independently of changes in the depression rating. Singh and Verma [42] treated 60 patients presenting with pain as the primary complaint in the absence of physical findings, to a psychiatric outpatient clinic using chlordiazepoxide, amitriptyline, or imipramine. Thse patients treated with either of the tricyclic antidepressants experienced significantly greater improvement than those medicated with chlordiazepoxide. Ward et al. [43] demonstrated the effectiveness of doxepin in reducing chronic pain in patients diagnosed as having a clinical depression. There was a significant relationship between the improvement of depression and the relief of pain. Bradley [44] divided 35 patients into two groups characterized by 1) the onset of pain prior to depressive symptoms, or 2) the onset of pain and depression simultaneously. When the patients were treated for depression, he found, in the first group, that the depression alone responded to treatment, and in the second group, both pain and depression were relieved simultaneously. However, Lindsay and Wychoff [45] demonstrated that 96 of 116 patients (83%) obtained significant pain relief associated with the antidepressant drug irrespective of the onset of pain and depression. In a double-blind crossover study, Pilowsky et al. [46] failed to demonstrate a reduction in pain in 32 patients using amitriptyline, as compared to a placebo. These patients were referred to a multidisciplinary pain clinic for the management of chronic pain where no organic cause of the pain could be detected.
Antidepressants/Chronic Pain
Discussion The most frequent antidepressants used in the following review are the ones that have significant serotonic uptake inhibition (doxepin, amitriptyline, clomipramine, and imipramine). This is congruent with the experimental evidence showing central nervous system serotonergic neurons involved in nociception [47]. Pain from chronic conditions such as migraine appear to be under tonic inhibition by pathways involving a serotonergic link. For example, plasma serotonic drops before the precipitation of migraine episodes [48], and parachlorophenylalanine, a serotonic synthesis inhibitor, triggers pain in migraine patients but not in controls [49]. Recent evidence, as summarized by Basbaum and Fields [50,51] provides a picture of a pain-activated inhibitory feedback circuit from the para-aqueductal gray area via the serotonergic raphe nucleus, which projects to primary pain sensory input areas such as lamina I and V of the spinal dorsal horn and the trigeminal caudalis. The pain-modulating pathways involve enkephalins and serotonin, as well as [51]. The noradrenergic neurotransmitters serotonergic pathways from the raphe appear to be at least partially in series with enkephalin, since naloxone can block raphe-induced analgesia [52]. Opiate analgesia is inhibited by serotonic depletion with neurotoxins [53], parachlorophenylalanine [54], or electrolytic lesions of the raphe [55,56]. Johansson 1571 found a positive correlation between levels of endorphins and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid of chronic pain patients. When these patients were treated with zimelidine, patients had significant relief of pain and reduction in levels of endorphins and 5HIAA, while no significant changes occurred with the placebo. In the studies [15,18,27,39,42,45] comparing the relative effectiveness of one antidepressant versus another, there is no single antidepressant that is more effective than the others for chronic pain states. There are some authors advocating the use of antidepressants in combination with phenothiazines [11,14,24,36-381, antiepileptic drugs [12], or lithium [9]. Unfortunately, these are case report studies and the effectiveness of antidepressants alone or in combination with other psychoactive drugs cannot be determined. The dose range of antidepressants most frequently reported in these studies is approximately of 50-100 mg per day. Except for clinical experi-
ence, it is unclear why this dose range, which is lower than that seen in primary depression, appears to be effective in chronic pain states. Only four studies [13,31,43,46] reported blood levels of tricyclic antidepressants. Using amitriptyline, Watson et al. [13] showed a decrease in pain levels in patients suffering from postherpetic neuralgia, with the mean plasma level of amitriptyline at 67 ng/ml and for nortriptyline at 38 ng/ml. The mean combined plasma level of amitriptyline and nortriptyline (105 ng/ml) is below the therapeutic ranges known for antidepressant effects. Hammeroff et al. (311 demonstrated improvement in depression and pain in patients with back pain, when the combined plasma level of doxepin and its metabolite desmethyldoxepin reached 70 ng/ml, below the therapeutic levels for endogenous depression. The lower dose range observed in clinical trials, and reports of lower therapeutic plasma thresholds of antidepressants seen in chronic pain-as compared to primary depression-may indicate that antidepressants work by a mechanism other than their mood-elevating activity in chronic pain states. In this review (see Table l), antidepressants used in 12 out of 16 clinical trials utilized in double-blind controlled studies with a placebo [5,8,23,27,30,31, 40,41,57] or crossover design [2,3,13,18,22,29,46] gave a greater than 55% improvement in the treatment of chronic pain. Four studies [8,30,40,46] showed equivocal results. Four out of four studies [ lO,ll, 19,421 employing consecutive-cases design showed a significant improvement with antidepressants in chronic pain. Nine studies [5,9,10,15, 24,27,29,31,44] have shown a direct correlation between an improvement in depression and chronic pain. However, five studies [13,18,20,23,41] have demonstrated pain relief without a parallel effect on depression. In three studies [2,3,22], when the authors excluded chronic pain patients with clinical evidence of depression, pain relief was obtained using antidepressants. Antidepressants were significantly effective in depressed patients with pain complaints in two studies [11,42]. Despite the frequent use of antidepressants in chronic pain, their mechanism of action is unknown. There are two major hypotheses regarding the therapeutic nature of antidepressants in chronic pain: 1) theory of direct or potentiated analgesic effects, and 2) theory of mood-activating property. In support of the direct analgesic theory, it is clinically observed that the effects of antidepressants in chronic pain are seen at lower dose ranges
59
Table 1 Improvement + Clinical state Author of study
Controlled study
Arthritis McDonald Scott (2) Gringras (3) Tyler (9)
Type of iv
dr% imipramine imipramine amitriptyline lithium lomipramine clomipramine
Yes Yes no
22 55 56
no Yes
41 49
no no
14 5
Hatangdi (12)
no
34
Watson (13) Diabetic neuropathy Davis (14)
Yes
22
no
8
Turkington (15)
Yes
59
Yes Yes Yes
16 100 280
Okasha (27)
Yes
80
Couch (20) Noone (21) Diamond (25) Sherwin (24)
no no Yes no
110 8 56 14
Facial pain Lascelles (29) Back pain
Yes
40
phenelzine
Jenkins (30) Hameroff (31)
Yes Yes
44 27
imipramine doxepin
no
28
various TCA’s
Regalando (7) Ganvir (8) Postherpetic neuralgia Woodforde (10) Taube (11)
Headaches Gomersall & Stuart (22) Couch (23) Curran and Lance (18)
Mixed etiologies Merskey (36) Kocher (37)
no
103
Carasso (39)
no
67
Evans (40) Johanssen (41) Pilowsky (46) Clarke (38)
Yes Yes Yes no
22 32 32
120
Dose (mg)
amitriptyline amitriptyline phenothiazine nortriptyline antiepileptics amitriptyline amitriptyline phenothiazine amitriptyline imipramine diazepam amitriptyline amitriptyline amitriptyline imipramine other drugs doxepin amitriptyline diazepam amitriptyline clomipramine amitriptyline amitriptyline perphenazine
phenothiazone various TCA’s phenothiazine clomipramine amitriptyline doxepin zimelidine amitriptyline amitriptyline perphenazine
Presence 0P depression
75 75 75
b b
Pain
Depression
C
60* 52* 79
? ? +
lo-25 25
a a
57 0
? ?
100 25-100
C C
79 100
+ ?
50-100
a
79
?
75
C
66*
-
100
?
100 100 15
C
100
+
lo-60 100 30-75 30-75
b
80* 55.3* 55*
-
30-50 30-150 6-10 75 30 lo-25 100-200 8-64
C
P
+
C
72 100
45 75 2.5 mg/kg
20-75 30-100 150 200 150 75 2
C C
a C C
P 70
? ? +
75*
+
0
0 +
C
93
?
a
92
?
a
54
?
0
0 -
C
C C
P
! 68
0 ?
*a, depression not examined; b, depressed patients excluded; c, depression diagnosed or rated. + results are statistically significant; p, mean scores (prey and post-test changes are statistically significant; 0, no difference pre- and post-test; ?, not reported; -, no correlation between improvements in pain and depression scores; +, direct relationship behveen improvement
60
in pain and depression
scores.
Antidepressants/Chronic Pain
and have more rapid onset of action than the response of antidepressants in depression [30]. Although the dose range of tricyclics in chronic pain patients is usually one-half that used to treat depression, the effects of tricyclics in chronic pain are seen in the first week of treatment, while effects on depression are usually delayed 3-4 weeks. Tricyclic antidepressants are thought to work by increasing levels of norepinephrine and serotonic by blocking their uptake by the presynaptic neurons. These neurotransmitters, especially serotonin, are involved in the descending spinal cord pathways, which inhibit pain transmission [51]. Hence, the tricyclic antidepressants may act directly on pain pathways. In addition, Couch [20,23] and Lance and Curran [18] have reported pain relief with tricyclics in chronic pain patients free of depression. Johansson [57] has shown pain alleviation without changes in depression ratings in patients with chronic pain treated with an antidepressant. For some time, it has been accepted that chronic pain patients often suffer from depression. Sternbath [58] has demonstrated high evidence of depression on MMPI’s in chronic pain patients. Merskey ]59] has diagnosed a high degree of secondary depression in patients with pain, and most recently Blumer [60] has theorized chronic pain as being a variant of depression. The beneficial effects of antidepressants as a result of their mood-elevating characteristics is evident in a number of studies showing a positive correlation between improvement in depression and pain relief [5,10,15,29]. In addition, Bradly [44] has shown that when pain begins with the onset of depression both can be relieved with treatment of the depression.
Summary Antidepressants are commonly used to treat chronic pain irregardless of etiology since the first report by Paoli [32] twenty-two years ago. However, there have been few controlled studies evaluating the efficacy of antidepressants in chronic pain. From the review, it is apparent that additional randomized controlled studies utilizing either doubleblind placebo or various methods should be done. This is important since the placebo response rate with tricyclics in depression is 47% [61]. To address the question of which neurotransmitter systems are important in pain inhibition, studies comparing the efficiency of norepinephrine reup-
take blocker (desipramine) versus serotonic reuptake blockers should be undertaken. Since there are overlaps in the clinical symptoms and treatment aspects of chronic pain and depression, any treatment outcome studies should control for and rate the type and degree of depression using reliable measures.
References 1. France RD, Houpt JL, Scott A, Varia I: Depression in chronic pain, in preparation 2. McDonald Scott WA: The relief of pain with an antidepressant in arthritis. The Practitioner 202:802-807, 1969 3. Gringas M: A clinical trial of tofranil in rheumatic pain in general practice. J Int Med Res 4:41-49, 1976 4. Haydu GG, Goldschmidt L, Drymiotis AD: Effects of imipramine on the rheumatoid factor titre of psychotic patients with depressive symptomatology. Ann Rheumatoid Dis 33:273-275, 1974 5. McNeil AL, Dick WL: Imipramine and rheumatoid factor. J Int Med Res 4:23-27, 1976 6. Regalado RG: Anafronil in the management of longterm pain: A preliminary report. J Int Med Res 4:54-55, 1976 7. Regalado RG: Clomipramine (Anafronil) and musculo-skeletal pain in general practice. J Int Med Res 5:72-77, 1977 8. Ganvir I’, Beaumont G, Seldrup J: A comparative trial of clomipramine and placebo: A adjunctive therapy in arthralgia. J Int Med Res 860-66, 1980 9. Tyler MA: Treatment of the painful shoulder syndrome with amitriptyline and lithium carbonate. Can Med Assoc J 111:137-140, 1974 10. Woodforde JM, Dwyer B, McElven BW et al: Treatment of postherpetic neuralgia. Med J Aust 2:869872, 1965 11. Taub A: Relief of postherpetic neuralgia with psychotropic drugs. J Neurosurgery 39:235-239, 1973 12. Hatangdi VS, Boas RA, Richard EG: Postherpetic neuralgia: Management with antiepileptic and tricyclic drugs. In Bonica JT, Albe-Fessard D (eds). Advances in Pain Research. New York, Raven Press, 1976, vol 1, pp. 583-587 13. Watson CP, Evans RJ, Reed K, et al: Amitriptyline versus placebo in postherpetic neuralgic. Neurology 32:671-673, 1982 14. Davis JL, Lewis SB, Gerick JE, Kaplan RA, Schultz TA, Wallin JD: Peripheral diabetic neuropathy treated with amitriptyline and fluphenazine. JAMA 23812291-2292, 1977 15. Turkington RW: Depression masquerading as diabetic neuropathy. JAMA 243:1147-1150, 1980 16. Mahloudji M: Prevention of migraine. Br Med J 1:182-183, 1969 17. Friedman AI’: The migraine syndrome. Bull N Y Acad Med 44:45-62, 1968 18. Lance JW, Curran DA: Treatment of chronic tension headache. Lancet 1:1236-1239, 1964 19. Dalession DJ: Chronic pain syndrome and disor-
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R. D. France, J. L. Houpt, and E. H. Ellinwood
20. 21. 22. 23. 24. 25. 26. 27. 28.
29. 30. 31.
32. 33. 34. 35. 36. 37. 38. 39. 40.
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Direct reprint request to: Randal D. France, M.D. Department of Psychiatry Box 3903 Duke Medical Center Durham, North Carolina 27710
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