- Email: [email protected]
On the putative efficacy of the antidepressants in chronic, benign pain syndromes
Focus
On the Putative Efficacy of the Antidepressants in Chronic, Benign Pain Syndromes An Update Karl Goodkin, *t Marietta A. E. Vrancken,t and Daniel Feaster*
Previous reviews of the use of antidepressant medication in the treatment of chronic, benign pain syndromes have reported significant analgesic effects in over 80% of subjects in less time and at lower doses than that required for the antidepressant effect. The authors' prior meta-analytic review did not support this effect, after controlling for trial quality. This article reports on an update of that review. The results are similar to those of the prior review, showing that 70% of trials again failed to meet minimal design and protocol criteria. Of the remainder, none met all four types of validity criteria used as an additional screening for trial quality. Improvement was noted in protocol (but not design) development and in the frequency of trials meeting at least two validity criteria. Key words: chronic pain, analgesia, antidepressants, meta-analysis, non-malignant pain
uch has been written in the past 30 years regarding the relationship between antidepressants and the treatment of chronic pain. Most reviews have been content oriented and have concluded that the antidepressant drugs typically demonstrate an analgesic effect in the treatment of chronic pain in less time and at lower doses than the antidepressant effect generally requires. As a result, these drugs have been promulgated for a variety of malignant and benign chronic pain syndromes.
M
From the 'University of Miami School of Medicine, Miami, FL and the tHelen Dowling Institute for Biopsychosocial Medicine, Rotterdam, The Netherlands. Reprint requests: Karl Goodkin, MD, PhD, Associate Professor of Psychiatry, Neurology and Psychology, Department of Psychiatry (M-836), University of Miami School of Medicine, 1400 NW 10th Avenue, No. 803-A, Miami, FL 33136.
Pain Forum 4(4): 237-247, 1995
In a review of chronic, benign pain syndromes 6 years ago, one of us (KG) conducted a meta-analysis critically examining the evidence for the efficacy of antidepressant drug treatment.' That review evaluated trials generated from a computer search of medical and psychological databases from 1976 to 1987 and included a few selected but frequently cited trials published prior to 1976. The minimum design criteria established for consideration of study results in efficacy analyses were designated for entry, randomization, control, baseline, blinding, carryover effects, and measurement. The entry criteria were that explicit inclusion and exclusion criteria be described fully and used. Randomization criteria included documentation of randomization and an adequate method, if described. The control criterion was the existence of a placebo control condition. The baseline criterion was that valid baseline measures were obtained (i.e., following a washout period) and that group differences at baseline were controlled for in the statistical analyses. The blinding criteria were that subjects, treatment providers, and assessors remained blind to treatment assignment throughout the trial and that threats to blinding were reported and evaluated (e.g., side effects). The carryover effects criteria applied for crossover designs and required that treatments be randomly counterbalanced with either a washout period (of at least 2 weeks) between treatments or sufficiently long periods for each treatment (i.e., 8 weeks or more) to eliminate the need for a washout period. These criteria also required that possible carryover effects be ruled out in statistical analyses of treatment efficacy. The measures criterion required that all dependent variables (DVs) be described in detail and be documented on their reliability and validity. The minimum protocol criteria established for consideration of study results in efficacy analyses were that all subjects received a
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standardized treatment, rules for setting and adjusting doses were established, and the schedule of assessments was described and followed. Of a total of 53 trials reviewed earlier,' 70% (37 trials) did not meet the minimum criteria designated for an adequate design or execution of the protocol, or both. Of these, almost all trials failed design criteria, whereas approximately two thirds (67%) also failed protocol criteria. For these trials, the design criteria causing failure in order of frequency were use of a predominant number of DVs of undetermined reliability and validity (18 trials), lack of a washout period between treatments or analysis of carryover effects (12 trials), lack of a baseline period or uncontrolled baseline differences (11 trials), lack of blind conditions (11 trials), inclusion/exclusion criteria inadequately specified (9 trials), undescribed or inadequate randomization (9 trials), and no or inadequate control group (4 trials). For protocol criteria, the reasons for failure were, in order of frequency, absence of a rigorous protocol (15 trials), an inadequately specified protocol (7 trials), breaking of blind conditions (2 trials), and unexecuted protocol (1 trial). These results included the special focus on 7 trials of chronic low back pain syndrome,' which has been questioned in terms of its potential analgesic response to antidepressant drug therapy. However, it should be noted that the orders of violated design and protocol criteria do not change when chronic low back pain syndrome trials are excluded, with the exception that the protocol criterion-breaking of blind conditionsbecomes equivalent in frequency to unexecuted protocol. Those trials that met design and protocol criteria were then subjected to a second level of review for quality of the trial based on validity issues developed by Cook and Campbell"; statistical conclusion validity (SCV), internal validity (IV), construct validity (CV), and external validity (EV). Briefly, SCV refers to the evidence that allows an inference that the independent and dependent measures are related (most frequently, the relation of conclusions made to the statistical results obtained). Internal validity refers to the evidence that there is a causal relationship between the variables manipulated (independent variable-the antidepressant medication tested) and those measured (dependent variablesmeasurements of pain treatment response). Construct validity refers to the qeneralizatlon that can be made from the actual measurement or manipulations used in a trial to abstract constructs and conceptual definitions (in this case of pain measures to pain treatment response). External validity refers to the scope of generalization that can be made beyond the specific sample. If subjects, settings, and conditions of a trial are applied to wider populations of persons, settings, or conditions (from samples to populations of patients with
specific chronic pain syndromes or across patients with differing chronic pain syndromes) (Figure). In our prior review,' none of the 16 trials meeting minimal criteria met all four types of additional validity criteria and 3 had violated all four, with SCV being most commonly violated (15 trials), followed by IV (10 trials), CV (7 trials), and EV (6 trials). Moreover, in the results of these trials, only 9 (56%) reported significant improvements in the principal measures of pain when the active drug was compared to placebo. However, 5 of the 7 trials (71%) on headache pain did report significant improvement in frequency, severity, or a weighted index combining these. Hence, it was concluded that there was no evidence for the analgesic efficacy of antidepressant drugs for chronic benign pain syndromes generally, nor for specific pain syndromes, with the exception of headache (regardless of migraine, tension, or mixed type). Regarding chronic low back pain syndrome trials specifically, we reviewed seven trials previously.' Five of these failed on the basis of the design and protocol criteria described above. In the other two trials there were significant limitations by validity criteria violations-failure of SCV, IV, and EV in one and failure of SCV and IV in the other. Because of the low number of chronic low back pain syndrome trials available to review, a separate comparison of specific design, protocol, and validity criteria with the larger sample was not justified. As
W e i 9 h t
i n 9
o f E f
f e
C
t
s
Design or Protocol Criteria Violated
4
3
2
1
0
1------------------------------------1 # of Validity Criteria' Violated
Trial Quality Figure. Weighting of effects is given to trials according to trial quality. Zero weighting is given to trials that are evaluated as having failed minimal design or protocol criteria. For trials that meet these criteria, weighting of trial results is given according to the number of four validity criteria violated (4-0: statistical conclusion, internal, external, and construct).
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only two trials met design and protocol criteria, it was concluded that an antidepressant medication effect on pain relief could not be supported in this syndrome. An update of the former review 7 is well beyond the scope of this article. Hence, we will focus here on the results of selected trials reported since 1987, with a similar format for review to that used in the prior review. However, we will focus specifically on articles selected from this literature search that have been cited frequently, published in journals with large readerships, or conducted by investigators cited in the prior review. As a result of this selective format, it must be pointed out that the results of this review cannot be considered to be equivalent to the prior review, which was based on all trials available from that literature search. Rather, this updated review is intended for illustrative purposes in examining the issues involved in critically evaluating antidepressant trials for chronic, benign pain syndromes so that valid conclusions may be drawn about their clinical utility as analgesic agents (independent of antidepressant or other effects). A literature search of Medline and PsychlNFO (an online version of Psychological Abstracts) databases using the key words "pain" and "antidepressive agents," limited to human studies and excluding neoplasms, yielded 38 trials. We have selected 17 (45%) for detailed review (Table). As seen in the Table, only 5 of 17 (29%) of the trials reviewed met design and protocol criteria cited in the prior review, a similar result to that review, in which 16 of 53 trials (30%) met these same criteria.' It might be suggested that such a similar finding in two separate reviews of the same topic area indicates bias in the review rather than consistency of the findings. Regarding this issue, it should be mentioned that two of the three reviewers did not participate in the prior review (MV, DF), and one of the prior reviewers was not involved in the current article (CG). Moreover, complete agreement by two of the three reviewers was required in order to characterize the studies included here (KG, MV). Hence, this reduces the likelihood of bias from the prior review accounting for the current findings. Nevertheless, as pointed out, these trials were selected by one of us (KG) from a larger group of trials identified by a literature search, and, therefore, cannot be considered to comprise a formal replication of the earlier finding. With this caveat reiterated, we may then compare the findings between these two reviews more closely. Of the 12 trials (71%) failing criteria for design or protocol here, all failed design criteria, and 3 failed protocol criteria. The design criteria failed were, in order of frequency, blinding (8 trials), measurement (7 trials), control (6 trials), carryover effects (6 trials), baseline (2 trials), ran-
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domization (1 trial) and entry criteria (1 trial). The frequencies of violation of the latter two criteria probably are underestimates due to difficulty in fully evaluating when these particular criteria were compromised based on the reports as published. When criteria could not be documented sufficiently on the basis of what was published, they were considered to be failed. Violations of protocol criteria evaluated were, in order of frequency, protocol inadequately specified (2 trials), unexecuted protocol (1 trial), absence of a rigorous protocol (0), and breaking of blind conditions (0). In addition, though not a protocol violation, a dosing protocol was used in one study in which the starting medication dose required reduction in one third of subjects." Interestingly, while the percentage of design criteria violated remained at the maximum possible level in the trials not meeting minimal criteria, the percentage of trials failing protocol criteria dropped from approximately two thirds (67%) to less than one third (25%). This suggests that there has been some improvement over the past 6 years in published trials of antidepressant drug therapy for chronic, benign pain syndromes. Though the proportion of trials failing design criteria of all trials not meeting minimal criteria was similar in the two reviews, differences were observed in the frequencies of specific design criteria failed. In this updated review, there were more frequent violations of blinding and control conditions and less frequent violation of a valid baseline period and control for baseline differences. It may be concluded there may have been some improvement in protocol development for antidepressant trials of chronic, benign pain syndromes over the past 6 years that has not been paralleled by improvement of design development. As aforementioned, 5 of 17 trials did meet the minimal design and protocol criteria for efficacy evaluation here. Two of these five trials showed significant results on pain outcome measures.v> two did not show significant results on the predominant number of outcome variables.?" and one showed significant results dependent on the pain syndrome examined (with efficacy for headache but not for chronic low back pain syndrome). 16 Hence, the overall result of this meta-analysis does not demonstrate evidence confirming the putative efficacy of antidepressants for chronic, benign pain syndromes. The trials meeting criteria for efficacy analysis were again evaluated on Cook and Campbell" validity criteria described above: SCV, IV, CV, and EV. As before,' none of the trials met all four validity criteria. However, none violated four or three criteria, while three studies violated two (60%),'2,13,33 and two studies violated only one criterion (40%).8,16 In the prior review, 3 of the 16 trials (19%) violated all four validity criteria, and 2 trials violated three criteria (12.5%), totaling 5 trials (31.5%) at this level of validity criteria violation. Nine trials (56%)
Table. Summary of antidepressant Reference Number and Study
Pain Syndrome Type
Drug
Dose/dey" (mg)
N§ 54 (30)
Ziegler et aI., 198732
Migraine headache
Amitriptyline Propranolol Placebo
50, 150 80,240
Eberhard et aI., 19884
Mixed chronic, benign" pain syndromes
Clomipramine Maprotiline
25, 150 50, 150
70 (52)
Max et aI., 1988"
Postherpetic neuralgia
Amitriptyline Lorazepam Lactose placebo
12.5, 150 0.5,6.0 250, 1500
62 (41)
Leijon and Bovie, 198915
Central poststroke pain
Amitriptyline Carbamazepine Lactulose placebo
25, 75 200,800
15 (14)
Mixed chronic, benign pain syndromes
Clomipramine Mianserin Placebo
75, 150 30,60
1990"#
Postherpetic neuralgia
Desipramine Benztropine placebo
12.5,250 0.5,1.0
26 (19)
Langemark et aI.,
Tension headache
Clomipramine Mianserin Placebo
75, 150 30, 60
114 (82)
7,7
Loldrup et aI., 1989 '6#
Kishore-Kumar et aI.,
199013#
?,7
7,7
253 (182)
7,7
Goodkin et aI., 19908#
Chronic low back pain
Trazodone Placebo
50, 600 50, 600
42 (41)
Nappi et aI., 1990"
Tension and mixed tension-migraine headache
Amitriptyline Ritanserin
50, 50 10, 10
38 (38)
Panerai et aI., 199024
Central pain (mostly "phantom limb")
Clomipramine Nortriptyline Placebo
25, 100 25, 100 25, 100
39 (24)
Pilowsky and Barrow,
Mixed chronic, benign pain syndromes
Amitriptyline + psychotherapy Amitriptyline + support Placebo + psychotherapy Placebo + support
7, 7
199025
240
7, ? ?, 7 7, 7
129 (102)
trials by criteria for entry into efficacy analysis Efficacy of Pain Relief
Trial Durationt (weeks)
Criteria Failed:/:
Comments
40, 10 for each drug
NA
D
Carryover effect not statistically evaluated; ? efficacy of blind; no report on control for narcotics use; no comparison of enrolled vs. completers
6
NA
D
No control group, DVs of undemonstrated reliability and validityll
12,6 for each drug
NA
D
All treatment orders not tested, with questionable rationale cited; 1 week washout period; DVs of not well established reliability and validity; study N not correctly represented (N = 62, not 58)
15,4for each drug
NA
D
? subject blind, as active drug side effects were> placebo (P < .05); DVs of unknown reliability and validity; washout period 1 week inadequate, despite low blood levels post-washout
6
Clomipramine and mianserin decreased VAS pain and global impression rating (P < .05), but only for tension headache by area-under-curve analysis of VAS while chronic low back pain patients improved on placebo; no effect for oral or abdominal pain (P < .05)
IV
Type of pain syndrome was critical to efficacy; results also differed by psychiatric status (anxiety vs. depressive syndromes); need to control for allowed oxazepam and paracetamol use; ? impact of baseline differences on sex and pain duration by pain syndrome
12, 6 on each drug
Desipramine decreased week 6 pain intensity scores (P < .001) and mechanical allodynia (P < .05)
SCV, IV
? blinding, given persisting side effect differences with active placebo at week 6; response greater with decreased pain duration; ? choice of week 6 only vs. entire treatment period as outcome measure; "intent to treat" analysis did not change findings
6
Decreased VAS pain ratings by primary area-under-curve analysis; non-significant results on 8 other efficacy tests
SCV, IV
Portion of same sample reported in Loldrup et al."; significant results reported based on only 1 of 9 tests conducted; need for experiment-wide error rate; significant placebo effects were noted on 2 of 3 outcome measures; as in Ref. 16, need control for allowed oxazepam (maximum 30 mg/d) and acetaminophen (maximum 1 gr tid) use
6
No significant differences on VAS pain, physical activity (by electronic monitor), pain rating while walking; no trazodone interaction with opioid analgesic intake; placebo group improved in dysfunction
EV
As blood level increased, VAS pain increased; double blind check confirmed integrity of blind; controlled for depression, opioid analgesic use, litigation status, source of recruitment, years of back pain and other pain sites, and baseline score on DVs; full compliance requirement to protocol reduces completers from 41 to 29
20, 12 on drug
NA
D,P
No control group used in design, though mentioned twice in reference to neurophysiological pain measures; protocol not well specified; "depressed only" inclusion criterion: Hamilton Rating Scale Depression 2 18.
9
NA
D
Latin square design used to balance ordersan advantage; however, no washout period and design eliminated first week of treatment in each cell with questionable rationale (despite start-up); ? blind, due to increased side effects with both antidepressants
12
NA
D,P
"Flexible" amitriptyline protocol inadequately described; no true control group without active treatment; ? consistent control for baseline differences; blind broken by subject, not fully maintained for non-drug treatment; DVs of unestablished reliability and validity; more response bias with comparative than absolute VAS; VAS administrations not completely standard; amitriptyline levels without metabolites (Table continues)
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Table. Reference Number and Study
Pain Syndrome Type
Dose/day' (mg)
Drug
N§
Zitman et aI., 199033#
Mixed chronic, benign pain syndromes
Amitriptyline (with riboflavin) Riboflavin placebo
25 (+5 riboflavin) 75 (+15 riboflavin) 5, 15
49 (39)
Max et aI., 199119
Diabetic neuropathy
Desipramine Benztropine placebo
12.5,250 0.5,1.0
24 (20)
Holroyd et aI., 1991"
Chronic tension headache
Amitriptyline Cognitive-behavioral therapy/relaxation training
25,75; 3 1-hour treatment sessions and 2 15minute phone contacts
41 (36)
McQuay et al., 199220
Mixed chronic, benign pain syndromes
Amitriptyline (sustained release) Placebo
25, 25
41 (23)
25,25
Watson et aI., 1992'0
Postherpetic neuralgia
Amitriptyline Maprotiline
37.5,150 50, 150
35 (32)
McQuay et aI., 1993"
Mixed chronic, benign pain syndromes
Amitriptyline (sustained release)
25,25 50, 50 75, 75
29 (18)
'Initial or minimum dose tested, target or maximum dose tested. [ Trial duration = weeks on trial, inlcuding washout periods. tD, design; P, protocol; SCV, statistical conclusion validity; IV, internal validity; EV, external validity. §Number in parentheses designates the number of completers. IIDV, dependent variable. #Studies meeting minimal design and protocol criteria for entry into the efficacy analysis.
violated two criteria, and 2 trials (12.5%) violated one criterion. Thus, in comparing trials violating three or four validity criteria between reviews, the number of trials violating a greater number of criteria appear to be decreased in this updated review. The validity criteria violated in the five trials meeting minimal design and protocol criteria here were, in order of frequency, IV (4 trials), SCV (2 trials), EV (2 trials), and CV (0). The latter probably is an underestimate due to our own specification for criterion violation, which accepts optimal pain measure sampling of the "pain construct" but does not require a multidimensional assessment of pain specifically mandating a combination of subjective, objective, and physiological pain measures in all trials. The issues concerning IV were related to controlling for impact of adverse event differences on blinding, placebo effects, effects of other prescribed medications that may have analgesic effects (e.g., benzodiazepines like oxazepam), type of pain syndrome, pain duration, and personality differences between groups. Issues concerning SCV involved mul-
tiple tests without citing an experiment-wide error rate and definition of pain outcome measures (Le., using the last week of the treatment period alone rather than the entire period). Issues involving EV included unusually long history of pain and unusually high prevalence of psychiatric disorders. Regarding the prior review,' the order of frequency (descending) of violation for 16 of 53 trials of these same criteria was SCV, IV, CV, and EV. Hence, it may be preliminarily concluded that more recent studies have improved somewhat in terms of attention to SCV and CV. However, the latter remains a source of concern, in that many studies still used predominantly subjective variables, though there was a better attempt to adequately describe the measures and cite appropriate sources for their reliability and validity than had been true in prior research. This, however, does not answer the remaining CV issue of a focus on subjective, self-report measures over more objective, rating measures (e.g., by blinded assessors with no other study duties). In addition, the focus on the subjective and objective domains occurs to the virtual exclu-
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243
Continued Trial Durationt (weeks) 6
12,
Efficacy of Pain Relief
Criteria Failed:/:
Decreased pain intensity (P < .02); no significant difference in activity nor analgesic intake
IV, EV
Though baseline differences were largely examined and controlled, no specific report of control for difference in personality variables; relatively high incidence of Axis I psychiatric disorders in sample; inclusion criteria regarding pain level unclear
NA
D
DVs of undemonstrated reliability and validity, no washout period; ? blind, as several side effects more frequent and persistent in desipramine group
NA
D
No true control group without active treatment; subjects not treated under blind conditions; medication protocol started at a dose where approximately 1/3 required dose reduction
NA
D, P
Protocol violated with 10 "completers" finishing only 1 of 3 weeks of treatment; 40% drop-out rate; ? blind, due to increased adverse events with amitriptyline (sedation; dry mouth); most DVs of questionable reliability and validity; no washout period
NA
D
No control group; ? blind, as different drugs had tablets of different shape and color and increased number and severity of adverse events with maprotiline; DVs largely subjective and of unestablished reliability and validity
NA
D
No true control group without active treatment; ? blind, due to side effect increase at 75 mg, though number of pills per day was controlled; no run-in period; subjects continued antidepressants during trial; unclear relation to prior study
6 on each drug 12
6,
3 weeks each condition
12,
5 on each drug
9,
Comments
3 three-week periods
sion of the physiological domain of pain measurement (e.g., nociceptive reflex threshold," physical activity by a computerized monitor," or allodynia"). A recommendation for future studies might still include, therefore, that DVs be selected that reflect these three domains of the "universe" of possible pain measures. Beyond the minimal design and protocol criteria described earlier, all of the validity criteria are important to the future planning of antidepressant trials for chronic, benign pain syndromes. The IV issues are of particular importance and are the most frequently violated of the validity criteria rated here. The violation of IV is directly relevant to the results of a trial, since IV refers to the evidence that there is a causal relationship between the antidepressant drug tested and the measurements of pain treatment response. Examples of violation of IV include the failure to control for other concurrent prescribed medications affecting pain; concurrent nonpharmacological treatments (e.g., neurosurgery, nerve blocks, transcutaneous electrical nerve stimulation units, cognitive behavioral therapy, behav-
ioral therapy, and other psychotherapy); as well as ongoing alcohol and recreational substance use in determining relation to outcome. In addition, threats to the blinding of a trial raise questions concerning IV, since knowledge of treatment assignment may then become an intervening variable biasing the direction of effects observed (exemplified by reference 12). The occurrence of significant placebo effects also represent a threat to IV, since the placebo effect itself becomes an intervening variable mediating the observable differences between treatment and "no treatment" groups (exemplified by reference 13). Numerous misconceptions exist regarding the placebo effect: about one third of patients will have a placebo effect in any clinical trial, the placebo effect is always brief, there is a placebo responder personality type, placebo responders have no primary pain disorder, and placebo administration is equivalent to no treatment." In reality, placebo response rates are quite variable (15-70% or more), placebo effects may last several years (e.g., in surgery trials), individuals tend not to be consistent
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about showing placebo response over placebo administrations, and placebo responses have definable pharmacokinetics as well as potential adverse effects (i.e., nocebo effects)." Placebo responses in antidepressant trials of chronic, benign pain syndromes are a particularly frequent problem. This is due .to the fact that many chronic, benign pain syndromes are intermittent by nature (e.g., chronic low back pain syndrome), many chronic pain subjects may seek out a trial when their pain is unusually severe (resulting in a problem of regression to the mean over the course of the trial), and pain subjects may be particularly liable to experience nonspecific treatment effects (e.g., such as those associated with provider warmth and interest as well as prestige of the treatment and setting). Another issue relevant to IV is that the type of pain syndrome examined may significantly impact the results of antidepressant drug treatment. This is particularly important in trials using samples with mixed types of chronic, benign pain syndromes.<,16,20,21,25,33 Although it had been previously concluded that trials of mixed chronic pain syndromes had decreased since 1983,' this review suggests that there has been a resurgence of such trials (35%). However, the prior rate of failure of minimal design and protocol criteria for such trials was 100%, whereas in this review it has decreased to 67%. Although it has been argued that such trials are specifically required to determine a syndrome-independent, analgesic effect of antidepressants," studies of mixed, chronic, benign pain syndromes are hampered by increased sample heterogeneity resulting in decreased statistical power. Finally, IV was affected here by lack of control for personality variables that may affect pain reports," baseline differences,"> mood disturbance (depression, anxiety, anger) within the normal ranqe," and psychiatric disorders." High drop-out rates (>40%)20 can also raise concern about trial IV due to bias related to protocol compliance factors. This IV concern can be significantly alleviated by the use of an "intention to treat" analysis." Consistent documentation of protocol compliance (e.g., by study drug8,20 and opioid analgesic pill counts," blood levels of study drug,8,12,15,16,18,19,25,30,33 and use of toxicology screens for alcohol and recreational substance use") would also substantiate IV and add to trial comparability in future studies. Documenting compliance with intake of other analqesic drugs can be helpful as well (e.g., non-narcotic [non-opioid] analgesics such as nonsteroidal anti-inflammatory drugs and benzodiazepines [oxazepam'<"] as either "no intake" or "continued intake at baseline levels throughout the trial"). In addition, statistical analyses can use controls for depression, opioid analgesic use, and litigation status defined as blocking factors in ANOVA.8 Testing the integrity of the blind by a report of a guess about treat-
ment assignment both by subject and evaluators can support the integrity of the blind and IV. Regarding SCV, improvements were noteworthy in the two most frequent violations in the area previously notedt-e-reliability of the DVs and report of the analyses in sufficient detail. However, several comments can again be made regarding the most commonly use subjective measure-the visual analog scale (VAS) for pain and other associated outcomes. Though previously? we had noted that VASs were rarely well specified, some improvement has occurred in this updated review in describing the VAS used in terms of absolute versus comparative type and calibration method. However, alternation of the poles of the scale to avoid response bias was not reported by any of these trials. Moreover, the use of a standardized instruction set and a training period for the subject to learn how to characterize his or her pain, for example, by acute and chronic components, in a reliable and valid manner were not discussed. In addition, scoring that optimally corrects for the high variability of this type of measure (e.g., slopes rather than means) received little attention. Such changes would further improve the SCV for VAS outcome variables in future trials. In addition, a greater focus remains to be established for other areas relevant to SCV. Important areas in this regard are proper methods of statistical analyses for repeated measures designs, methods appropriate to the measurement level of the variable, and the use of multiple significance tests without adjustment of the type I error rate. Nearly 50% (8/17) of the trials used a crossover design.'2,15,18-2,,30,32 For such designs repeated measures ANOVA takes advantage of the power inherent in using subjects as their own control, while allowing for a correction for period effects. The test for carryover effect in a twoperiod crossover and the clear lack of such an effect are prerequisites for a valid test of drug treatment effect. This analysis was properly used in interpretation of results in three of the eight crossover trials. '8,30,32 Another issue in evaluating SCV involves choice of statistical analysis where multiple outcome measures of pain are utilized. In a crossover design, where repeated measures ANOVA is indicated, consideration of multiple DVs should either use a corrected a or analysis of a composite index. In a non-crossover design, where repeated measure ANOVA mayor may not be advantageous and sample size is adequate, simultaneous analyses of multiple variables by MANOVA is preferable to multiple univariate analyses." Choice of statistical analyses appropriate to the measurement level of the outcome variable (Le., nominal, ordinal, interval, or ratio) can also be improved on. '3,15 Specifically, if outcome is measured on an interval or ratio scale, then parametric statistics are preferable, unless sample distribution
FOGUS/Goodkin et al.
anomalies preclude their use (e.g., deviations from normality or whatever other theoretical distribution is required by the statistical test used). Regarding EV, the scope of generalization that can be made beyond the specific sample, two trials are relevant here. 8 ,33 In one trial," EV was limited by the "superchronic" sample recruited, with a history of chronic low back pain syndrome of 20.3 years from the first reported episode. Site of recruitment was also a source of variance in this trial. However, both of these variables were controlled for in the statistical analyses conducted," Another study" raised concern about EV due to a high prevalence of psychiatric disorders (51%) in the sample. In general, more attention should be paid to issues relating to EV in future trials, for example, the influence of the sociodemographic characteristics of the particular subjects recruited, as well as the setting and conditions of the trial. Comparison of sociodemographic characteristics of dropouts versus completers and those enrolled versus those approached who refused enrollment can aid in the support of trial EV. For example, ethnicity is a relevant variable relating to cultural influences on pain reportinq." In conclusion, the use of antidepressant medication for analgesia in chronic pain syndrome patients has become a clinical nostrum in recent years. For example, a quick reference guide for clinicians on cancer pain states that antidepressants have "innate analgesic properties" and "are useful in pharmacological management of neuropathic pain" (also commonly seen in chronic, benign pain syndromes)." It is also stated that amitriptyline is the "tricyclic agent of choice" for this indication. Although prior reviews of antidepressant medication for chronic, benign pain syndromes concluded that the response rate averages 83% in this setting,' critical evaluation of the literature based on meta-analytic review has been reported only infrequently. Such reports have been consistent recently in suggesting that the antidepressant drugs may, indeed, have an analgesic effect (though this is disputed), but that the magnitude of the effects may be smaller than previously thought and appear to be quite modest,":" if present.'> In addition, there has been more recognition of the methodological limitations of published studies in metaanalytic reviews.7,23,27 One problem in this area is that there may be numerous unpublished trials with nonsignificant effect sizes-the "file drawer" problem. Statistical correction for this problem specifying a "fail safe N" has been published" and should be used in future meta-analyses. It must also be considered that, in many instances, comments cited in the Table and in our prior review' are based on the limitations of published reports imposed by journal reviewers and editors upon the investigators. Specific issues related to presentation of
245
missing data, comparative analyses with those refusing enrollment, and detailed presentations of control variables are relevant in this regard. Such limitations should, perhaps, be reconsidered by journal reviewers and editorial boards. With the foregoing limitations acknowledged, this updated review of the analgesic efficacy of antidepressants for chronic, benign pain syndromes confirms that antidepressants cannot be concluded to be a generally effective treatment modality, although we previously have reported that they might be effective for headache.' Chronic low back pain syndrome has been examined specifically in several reviews, with negative conclusions about the analgesic efficacy of antidepressants.v"> Interestingly, depressed mood and decreased functional status, but not pain intensity, have been associated with somatic complaints in chronic low back pain syndrome patients. ' Given the above conclusion, what, then, might be the most appropriate clinical guidelines to set forth for prescribing antidepressant pharmacotherapy in chronic, benign pain syndrome patients? First, it should be emphasized that the treatment of chronic, benign pain syndromes (as with other chronic medical illnesses) is best proposed from the broad standpoint of a multidisciplinary framework involving the biological, psychodynamic, behavioral, sociocultural, and phenomenological determinants of pain complaints as well as other pain behaviors, as described by numerous investigators. 5,6,25,29 Within this broad scope of relevant intervention at these five levels, antidepressant pharmacotherapy is properly conceived as one possible intervention at the biological level. Once an intervention at the biological level has been included in the pain management plan following the thorough multidisciplinary investigation of the specific patient's needs, comparative interventions at this level then may be considered, depending on the specific pain syndrome involved (e.g., transcutaneous electrical nerve stimulation units, peripheral nerve blocks, trigger point injection, neurosurgery, physical therapy, and pharmacotherapy, including opioids, neuroleptics, anticonvulsants, psychostirriulants, and antidepressants). It may reasonably be stated that an indication for antidepressant pharmacotherapy is a coexisting psychiatric disorder responsive to such treatment (e.g., major depressive disorder)." It may also be concluded that headache pain (regardless of depressive disorder) should be considered an indication as we11. 7,17,23 Finally, chronic, benign pain syndromes associated with other disorders may be considered for antidepressant treatment, but only after the failure of all other treatment options accessible and indicated for the specific syndrome involved. This conclusion promulgates a more circumscribed role for the use of antidepressant pharmacotherapy than has been advocated generally. It has been suggested that this
246
FOCUS/Goodkin et al.
conclusion is "counter to the experience of most practitioners"." Though this has not invariably been found," this suggestion may, indeed, be true. Yet, the purpose of a clinical trial is to conduct a prospective study in which a treatment is compared to a control condition for the express purpose of differentiating -an experimentally valid observation from clinical observation, which is clearly subject to bias regardless of the breadth of its consensus. It has also been suggested that the "minimal" design and protocol criteria used here are simply too rigorous to require for entry into an efficacy analysis, especially after the validity criteria are superimposed. Yet psychopharmacological drug trials generally, and analgesic trials particularly, have been plagued by confounding variables of a wide variety of types-eoncomitant medications affecting pain, pain syndrome heterogeneity, high drop-out rates, and differential side effects, placebo response patterns, ethnic pain responses, and pain outcome measure scope and choices, to name several. Hence, we submit that criteria like those adopted here are necessary to achieve the goal of correctly inferring conclusions about the results of the current literature concerning the putative analgesic efficacy of antidepressant medication for chronic, benign pain syndromes. Therefore, it is with these caveats that we put forth the aforementioned clinical guidelines based upon the current state of knowledge.
References 1. Bacon NMK, Bacon SF, Atkinson JH et al: Somatization symptoms in chronic low back pain patients. Psychosom Med 56:118-127,1994 2. Cook TO, Campbell DT: Quasi-experimental design and analysis issues in field settings. Houghton Mifflin, Boston, 1979 3. Department of Health and Human Services (DHHS), Public Health Service, Agency for Health Care Policy and Research: Management of cancer pain: adults. NO.9. Quick reference guide for clinicians. Clinical practice guideline. (AHCPR Publication No. 94-0593). US DHHS, Rockville, 1994 4. Eberhard G, von Knorring L, Nilsson HL et al: A doubleblind randomized study of clomipramine versus maprotiline in patients with idiopathic pain syndromes. Neuropsychobiology 19:25-34, 1988 5. Flor H, Fydrich T, Turk ClY. Efficacy of multidisciplinary pain treatment centers: a meta-analytic review. Pain 49:221-230,1992 6. Goodkin K: Coping with chronic pain: a guide to patient self-management. Book review. J Clin Psychopharmacol 10:445, 1990 7. Goodkin K, Gullion C: Antidepressants for the relief of chronic pain: do they work? Ann Behav Med 11 :83-101, 1989
8. Goodkin K, Gullion C, Agras WS: A randomized, doubleblind, placebo-controlled trial of trazodone hydrochloride in chronic low back pain syndrome. J Clin Psychopharmacol 10:269-278, 1990 9. Greenwald HP: Interethnic differences in pain perception. Pain 44:157-163,1991 10. Haddox JD: Antidepressant use in chronic pain syndromes. pp. 2-3. In Berde CB (ed): Technical Corner, International Association for the Study of Pain (IASP) Newsletter. November/December. IASP, Seattle, 1990 11. Holroyd KA, Nash JM, Pingel JD: A comparison of pharmacological (amitriptyline HCL) and nonpharmacological (cognitive-behavioral) therapies for chronic tension headaches. J Consult Clin PsychoI59:387-393, 1991 12. Kishore-Kumar R, Max MB, Schafer SC et al: Desipramine relieves postherpetic neuralgia. Clin Pharmacol Ther 47:305-312, 1990 13. Langemark M, Loldrup 0, Bech P, Olesen J: Clomipramine and mianserin in the treatment of chronic tension headache: a double-blind, controlled study. Headache 30:118-121, 1990 14. Large RG: The psychiatrist and the chronic pain patient: 172 anecdotes. Pain 9:253-263, 1980 15. Leijon G, Bovie J: Central post-stroke pain: a controlled trial of amitriptyline and carbamazepine. Pain 36:27-36, 1989 16. Loldrup 0, Langemark M, Hansen HJ, Olesen J, Bech P: Clomipramine and mianserin in chronic idiopathic pain syndrome: a placebo controlled study. Psychopharmacology 99:1-7,1989 17. Magni G: The use of antidepressants in the treatment of chronic pain: a review of the current evidence. Drugs 42:730-748,1991 18. Max MS, Schafer SC, Culnane M et al: Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology 38:1427-1432,1988 19. Max MB, Kishore-Kumar R, Schafer SC et al: Efficacy of desipramine in painful diabetic neuropathy: a placebocontrolled trial. Pain 45:3-9, 1991 20. McQuay HJ, Carroll 0, Glynn CJ: Low dose amitriptyline in the treatment of chronic pain. Anaesthesia 47:646-652, 1992 21. McQuay HJ, Carroll 0, Glynn CJ: Dose-response for analgesic effect of amitriptyline in chronic pain. Anaesthesia 48:281-285,1993 22. Nappi G, Sandrini G, Granella F et al: A new 5-HT2 antagonist (ritanserin) in the treatment of chronic headache with depression: a double-blind study vs. amitriptyline. Headache 30:439-444, 1990 23. Onghena P, Van Houdenhove B: Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebo-controlled studies. Pain 49:205-209, 1992 24. Panerai AE, Monza G, Movilia P et al: A randomized, within-patient, cross-over, placebo-controlled trial on the efficacy and tolerability of the tricyclic antidepressants clorimipramine and nortriptyline in central pain. Acta Neurol Scand 82:34-38, 1990
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25. Pilowsky I, Barrow CG: A controlled study of psychotherapy and amitriptyline used individually and in combination in the treatment of chronic intractable, 'psychogenic' pain. Pain 40:3-19, 1990 26. Rosenthal R: Meta-analysis: a review. Psychosom Med 53:247-271, 1991 27. Turner JA, Denny MC: Do antidepressant medications relieve chronic low back pain? J Fam Pract 37: 545-553,1993 28. Turner JA, Deyo RA, Loeser JD, Von Korff M, Fordyce WE: The importance of placebo effects in pain treatment and research. JAMA271:1609-1614, 1994 29. Vrancken MAE: Schools of thought on pain. Section M. Soc Sci Med 29:435-444, 1989
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30. Watson CPN, Chipman M, Reed K, Evans RJ, Birkett N: Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial. Pain 48:2936, 1992 31. White K, Kando J, Park T, Waternaux C, Brown WA: Side effects and the "blindability" of clinical drug trials. Am J Psychiatry 149:1730-1731,1992 32. Ziegler OK, Hurwitz A, Hassanein RS et al: Migraine prophylaxis: a comparison of propranolol and amitriptyline Arch Neurol 44:486-489, 1987 33. Zitman FG, Linssen ACG, Edelbroek PM, Stijnen T: Low dose amitriptyline in chronic pain: the gain is modest. Pain 42:35-42, 1990
On the Putative Efficacy of the Antidepressants in Chronic, Benign Pain Syndromes An Update Karl Goodkin, *t Marietta A. E. Vrancken,t and Daniel Feaster*
Previous reviews of the use of antidepressant medication in the treatment of chronic, benign pain syndromes have reported significant analgesic effects in over 80% of subjects in less time and at lower doses than that required for the antidepressant effect. The authors' prior meta-analytic review did not support this effect, after controlling for trial quality. This article reports on an update of that review. The results are similar to those of the prior review, showing that 70% of trials again failed to meet minimal design and protocol criteria. Of the remainder, none met all four types of validity criteria used as an additional screening for trial quality. Improvement was noted in protocol (but not design) development and in the frequency of trials meeting at least two validity criteria. Key words: chronic pain, analgesia, antidepressants, meta-analysis, non-malignant pain
uch has been written in the past 30 years regarding the relationship between antidepressants and the treatment of chronic pain. Most reviews have been content oriented and have concluded that the antidepressant drugs typically demonstrate an analgesic effect in the treatment of chronic pain in less time and at lower doses than the antidepressant effect generally requires. As a result, these drugs have been promulgated for a variety of malignant and benign chronic pain syndromes.
M
From the 'University of Miami School of Medicine, Miami, FL and the tHelen Dowling Institute for Biopsychosocial Medicine, Rotterdam, The Netherlands. Reprint requests: Karl Goodkin, MD, PhD, Associate Professor of Psychiatry, Neurology and Psychology, Department of Psychiatry (M-836), University of Miami School of Medicine, 1400 NW 10th Avenue, No. 803-A, Miami, FL 33136.
Pain Forum 4(4): 237-247, 1995
In a review of chronic, benign pain syndromes 6 years ago, one of us (KG) conducted a meta-analysis critically examining the evidence for the efficacy of antidepressant drug treatment.' That review evaluated trials generated from a computer search of medical and psychological databases from 1976 to 1987 and included a few selected but frequently cited trials published prior to 1976. The minimum design criteria established for consideration of study results in efficacy analyses were designated for entry, randomization, control, baseline, blinding, carryover effects, and measurement. The entry criteria were that explicit inclusion and exclusion criteria be described fully and used. Randomization criteria included documentation of randomization and an adequate method, if described. The control criterion was the existence of a placebo control condition. The baseline criterion was that valid baseline measures were obtained (i.e., following a washout period) and that group differences at baseline were controlled for in the statistical analyses. The blinding criteria were that subjects, treatment providers, and assessors remained blind to treatment assignment throughout the trial and that threats to blinding were reported and evaluated (e.g., side effects). The carryover effects criteria applied for crossover designs and required that treatments be randomly counterbalanced with either a washout period (of at least 2 weeks) between treatments or sufficiently long periods for each treatment (i.e., 8 weeks or more) to eliminate the need for a washout period. These criteria also required that possible carryover effects be ruled out in statistical analyses of treatment efficacy. The measures criterion required that all dependent variables (DVs) be described in detail and be documented on their reliability and validity. The minimum protocol criteria established for consideration of study results in efficacy analyses were that all subjects received a
237
238
FOCUS/Goodkin et al.
standardized treatment, rules for setting and adjusting doses were established, and the schedule of assessments was described and followed. Of a total of 53 trials reviewed earlier,' 70% (37 trials) did not meet the minimum criteria designated for an adequate design or execution of the protocol, or both. Of these, almost all trials failed design criteria, whereas approximately two thirds (67%) also failed protocol criteria. For these trials, the design criteria causing failure in order of frequency were use of a predominant number of DVs of undetermined reliability and validity (18 trials), lack of a washout period between treatments or analysis of carryover effects (12 trials), lack of a baseline period or uncontrolled baseline differences (11 trials), lack of blind conditions (11 trials), inclusion/exclusion criteria inadequately specified (9 trials), undescribed or inadequate randomization (9 trials), and no or inadequate control group (4 trials). For protocol criteria, the reasons for failure were, in order of frequency, absence of a rigorous protocol (15 trials), an inadequately specified protocol (7 trials), breaking of blind conditions (2 trials), and unexecuted protocol (1 trial). These results included the special focus on 7 trials of chronic low back pain syndrome,' which has been questioned in terms of its potential analgesic response to antidepressant drug therapy. However, it should be noted that the orders of violated design and protocol criteria do not change when chronic low back pain syndrome trials are excluded, with the exception that the protocol criterion-breaking of blind conditionsbecomes equivalent in frequency to unexecuted protocol. Those trials that met design and protocol criteria were then subjected to a second level of review for quality of the trial based on validity issues developed by Cook and Campbell"; statistical conclusion validity (SCV), internal validity (IV), construct validity (CV), and external validity (EV). Briefly, SCV refers to the evidence that allows an inference that the independent and dependent measures are related (most frequently, the relation of conclusions made to the statistical results obtained). Internal validity refers to the evidence that there is a causal relationship between the variables manipulated (independent variable-the antidepressant medication tested) and those measured (dependent variablesmeasurements of pain treatment response). Construct validity refers to the qeneralizatlon that can be made from the actual measurement or manipulations used in a trial to abstract constructs and conceptual definitions (in this case of pain measures to pain treatment response). External validity refers to the scope of generalization that can be made beyond the specific sample. If subjects, settings, and conditions of a trial are applied to wider populations of persons, settings, or conditions (from samples to populations of patients with
specific chronic pain syndromes or across patients with differing chronic pain syndromes) (Figure). In our prior review,' none of the 16 trials meeting minimal criteria met all four types of additional validity criteria and 3 had violated all four, with SCV being most commonly violated (15 trials), followed by IV (10 trials), CV (7 trials), and EV (6 trials). Moreover, in the results of these trials, only 9 (56%) reported significant improvements in the principal measures of pain when the active drug was compared to placebo. However, 5 of the 7 trials (71%) on headache pain did report significant improvement in frequency, severity, or a weighted index combining these. Hence, it was concluded that there was no evidence for the analgesic efficacy of antidepressant drugs for chronic benign pain syndromes generally, nor for specific pain syndromes, with the exception of headache (regardless of migraine, tension, or mixed type). Regarding chronic low back pain syndrome trials specifically, we reviewed seven trials previously.' Five of these failed on the basis of the design and protocol criteria described above. In the other two trials there were significant limitations by validity criteria violations-failure of SCV, IV, and EV in one and failure of SCV and IV in the other. Because of the low number of chronic low back pain syndrome trials available to review, a separate comparison of specific design, protocol, and validity criteria with the larger sample was not justified. As
W e i 9 h t
i n 9
o f E f
f e
C
t
s
Design or Protocol Criteria Violated
4
3
2
1
0
1------------------------------------1 # of Validity Criteria' Violated
Trial Quality Figure. Weighting of effects is given to trials according to trial quality. Zero weighting is given to trials that are evaluated as having failed minimal design or protocol criteria. For trials that meet these criteria, weighting of trial results is given according to the number of four validity criteria violated (4-0: statistical conclusion, internal, external, and construct).
FOCUS/Goodkin et al.
only two trials met design and protocol criteria, it was concluded that an antidepressant medication effect on pain relief could not be supported in this syndrome. An update of the former review 7 is well beyond the scope of this article. Hence, we will focus here on the results of selected trials reported since 1987, with a similar format for review to that used in the prior review. However, we will focus specifically on articles selected from this literature search that have been cited frequently, published in journals with large readerships, or conducted by investigators cited in the prior review. As a result of this selective format, it must be pointed out that the results of this review cannot be considered to be equivalent to the prior review, which was based on all trials available from that literature search. Rather, this updated review is intended for illustrative purposes in examining the issues involved in critically evaluating antidepressant trials for chronic, benign pain syndromes so that valid conclusions may be drawn about their clinical utility as analgesic agents (independent of antidepressant or other effects). A literature search of Medline and PsychlNFO (an online version of Psychological Abstracts) databases using the key words "pain" and "antidepressive agents," limited to human studies and excluding neoplasms, yielded 38 trials. We have selected 17 (45%) for detailed review (Table). As seen in the Table, only 5 of 17 (29%) of the trials reviewed met design and protocol criteria cited in the prior review, a similar result to that review, in which 16 of 53 trials (30%) met these same criteria.' It might be suggested that such a similar finding in two separate reviews of the same topic area indicates bias in the review rather than consistency of the findings. Regarding this issue, it should be mentioned that two of the three reviewers did not participate in the prior review (MV, DF), and one of the prior reviewers was not involved in the current article (CG). Moreover, complete agreement by two of the three reviewers was required in order to characterize the studies included here (KG, MV). Hence, this reduces the likelihood of bias from the prior review accounting for the current findings. Nevertheless, as pointed out, these trials were selected by one of us (KG) from a larger group of trials identified by a literature search, and, therefore, cannot be considered to comprise a formal replication of the earlier finding. With this caveat reiterated, we may then compare the findings between these two reviews more closely. Of the 12 trials (71%) failing criteria for design or protocol here, all failed design criteria, and 3 failed protocol criteria. The design criteria failed were, in order of frequency, blinding (8 trials), measurement (7 trials), control (6 trials), carryover effects (6 trials), baseline (2 trials), ran-
239
domization (1 trial) and entry criteria (1 trial). The frequencies of violation of the latter two criteria probably are underestimates due to difficulty in fully evaluating when these particular criteria were compromised based on the reports as published. When criteria could not be documented sufficiently on the basis of what was published, they were considered to be failed. Violations of protocol criteria evaluated were, in order of frequency, protocol inadequately specified (2 trials), unexecuted protocol (1 trial), absence of a rigorous protocol (0), and breaking of blind conditions (0). In addition, though not a protocol violation, a dosing protocol was used in one study in which the starting medication dose required reduction in one third of subjects." Interestingly, while the percentage of design criteria violated remained at the maximum possible level in the trials not meeting minimal criteria, the percentage of trials failing protocol criteria dropped from approximately two thirds (67%) to less than one third (25%). This suggests that there has been some improvement over the past 6 years in published trials of antidepressant drug therapy for chronic, benign pain syndromes. Though the proportion of trials failing design criteria of all trials not meeting minimal criteria was similar in the two reviews, differences were observed in the frequencies of specific design criteria failed. In this updated review, there were more frequent violations of blinding and control conditions and less frequent violation of a valid baseline period and control for baseline differences. It may be concluded there may have been some improvement in protocol development for antidepressant trials of chronic, benign pain syndromes over the past 6 years that has not been paralleled by improvement of design development. As aforementioned, 5 of 17 trials did meet the minimal design and protocol criteria for efficacy evaluation here. Two of these five trials showed significant results on pain outcome measures.v> two did not show significant results on the predominant number of outcome variables.?" and one showed significant results dependent on the pain syndrome examined (with efficacy for headache but not for chronic low back pain syndrome). 16 Hence, the overall result of this meta-analysis does not demonstrate evidence confirming the putative efficacy of antidepressants for chronic, benign pain syndromes. The trials meeting criteria for efficacy analysis were again evaluated on Cook and Campbell" validity criteria described above: SCV, IV, CV, and EV. As before,' none of the trials met all four validity criteria. However, none violated four or three criteria, while three studies violated two (60%),'2,13,33 and two studies violated only one criterion (40%).8,16 In the prior review, 3 of the 16 trials (19%) violated all four validity criteria, and 2 trials violated three criteria (12.5%), totaling 5 trials (31.5%) at this level of validity criteria violation. Nine trials (56%)
Table. Summary of antidepressant Reference Number and Study
Pain Syndrome Type
Drug
Dose/dey" (mg)
N§ 54 (30)
Ziegler et aI., 198732
Migraine headache
Amitriptyline Propranolol Placebo
50, 150 80,240
Eberhard et aI., 19884
Mixed chronic, benign" pain syndromes
Clomipramine Maprotiline
25, 150 50, 150
70 (52)
Max et aI., 1988"
Postherpetic neuralgia
Amitriptyline Lorazepam Lactose placebo
12.5, 150 0.5,6.0 250, 1500
62 (41)
Leijon and Bovie, 198915
Central poststroke pain
Amitriptyline Carbamazepine Lactulose placebo
25, 75 200,800
15 (14)
Mixed chronic, benign pain syndromes
Clomipramine Mianserin Placebo
75, 150 30,60
1990"#
Postherpetic neuralgia
Desipramine Benztropine placebo
12.5,250 0.5,1.0
26 (19)
Langemark et aI.,
Tension headache
Clomipramine Mianserin Placebo
75, 150 30, 60
114 (82)
7,7
Loldrup et aI., 1989 '6#
Kishore-Kumar et aI.,
199013#
?,7
7,7
253 (182)
7,7
Goodkin et aI., 19908#
Chronic low back pain
Trazodone Placebo
50, 600 50, 600
42 (41)
Nappi et aI., 1990"
Tension and mixed tension-migraine headache
Amitriptyline Ritanserin
50, 50 10, 10
38 (38)
Panerai et aI., 199024
Central pain (mostly "phantom limb")
Clomipramine Nortriptyline Placebo
25, 100 25, 100 25, 100
39 (24)
Pilowsky and Barrow,
Mixed chronic, benign pain syndromes
Amitriptyline + psychotherapy Amitriptyline + support Placebo + psychotherapy Placebo + support
7, 7
199025
240
7, ? ?, 7 7, 7
129 (102)
trials by criteria for entry into efficacy analysis Efficacy of Pain Relief
Trial Durationt (weeks)
Criteria Failed:/:
Comments
40, 10 for each drug
NA
D
Carryover effect not statistically evaluated; ? efficacy of blind; no report on control for narcotics use; no comparison of enrolled vs. completers
6
NA
D
No control group, DVs of undemonstrated reliability and validityll
12,6 for each drug
NA
D
All treatment orders not tested, with questionable rationale cited; 1 week washout period; DVs of not well established reliability and validity; study N not correctly represented (N = 62, not 58)
15,4for each drug
NA
D
? subject blind, as active drug side effects were> placebo (P < .05); DVs of unknown reliability and validity; washout period 1 week inadequate, despite low blood levels post-washout
6
Clomipramine and mianserin decreased VAS pain and global impression rating (P < .05), but only for tension headache by area-under-curve analysis of VAS while chronic low back pain patients improved on placebo; no effect for oral or abdominal pain (P < .05)
IV
Type of pain syndrome was critical to efficacy; results also differed by psychiatric status (anxiety vs. depressive syndromes); need to control for allowed oxazepam and paracetamol use; ? impact of baseline differences on sex and pain duration by pain syndrome
12, 6 on each drug
Desipramine decreased week 6 pain intensity scores (P < .001) and mechanical allodynia (P < .05)
SCV, IV
? blinding, given persisting side effect differences with active placebo at week 6; response greater with decreased pain duration; ? choice of week 6 only vs. entire treatment period as outcome measure; "intent to treat" analysis did not change findings
6
Decreased VAS pain ratings by primary area-under-curve analysis; non-significant results on 8 other efficacy tests
SCV, IV
Portion of same sample reported in Loldrup et al."; significant results reported based on only 1 of 9 tests conducted; need for experiment-wide error rate; significant placebo effects were noted on 2 of 3 outcome measures; as in Ref. 16, need control for allowed oxazepam (maximum 30 mg/d) and acetaminophen (maximum 1 gr tid) use
6
No significant differences on VAS pain, physical activity (by electronic monitor), pain rating while walking; no trazodone interaction with opioid analgesic intake; placebo group improved in dysfunction
EV
As blood level increased, VAS pain increased; double blind check confirmed integrity of blind; controlled for depression, opioid analgesic use, litigation status, source of recruitment, years of back pain and other pain sites, and baseline score on DVs; full compliance requirement to protocol reduces completers from 41 to 29
20, 12 on drug
NA
D,P
No control group used in design, though mentioned twice in reference to neurophysiological pain measures; protocol not well specified; "depressed only" inclusion criterion: Hamilton Rating Scale Depression 2 18.
9
NA
D
Latin square design used to balance ordersan advantage; however, no washout period and design eliminated first week of treatment in each cell with questionable rationale (despite start-up); ? blind, due to increased side effects with both antidepressants
12
NA
D,P
"Flexible" amitriptyline protocol inadequately described; no true control group without active treatment; ? consistent control for baseline differences; blind broken by subject, not fully maintained for non-drug treatment; DVs of unestablished reliability and validity; more response bias with comparative than absolute VAS; VAS administrations not completely standard; amitriptyline levels without metabolites (Table continues)
241
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Table. Reference Number and Study
Pain Syndrome Type
Dose/day' (mg)
Drug
N§
Zitman et aI., 199033#
Mixed chronic, benign pain syndromes
Amitriptyline (with riboflavin) Riboflavin placebo
25 (+5 riboflavin) 75 (+15 riboflavin) 5, 15
49 (39)
Max et aI., 199119
Diabetic neuropathy
Desipramine Benztropine placebo
12.5,250 0.5,1.0
24 (20)
Holroyd et aI., 1991"
Chronic tension headache
Amitriptyline Cognitive-behavioral therapy/relaxation training
25,75; 3 1-hour treatment sessions and 2 15minute phone contacts
41 (36)
McQuay et al., 199220
Mixed chronic, benign pain syndromes
Amitriptyline (sustained release) Placebo
25, 25
41 (23)
25,25
Watson et aI., 1992'0
Postherpetic neuralgia
Amitriptyline Maprotiline
37.5,150 50, 150
35 (32)
McQuay et aI., 1993"
Mixed chronic, benign pain syndromes
Amitriptyline (sustained release)
25,25 50, 50 75, 75
29 (18)
'Initial or minimum dose tested, target or maximum dose tested. [ Trial duration = weeks on trial, inlcuding washout periods. tD, design; P, protocol; SCV, statistical conclusion validity; IV, internal validity; EV, external validity. §Number in parentheses designates the number of completers. IIDV, dependent variable. #Studies meeting minimal design and protocol criteria for entry into the efficacy analysis.
violated two criteria, and 2 trials (12.5%) violated one criterion. Thus, in comparing trials violating three or four validity criteria between reviews, the number of trials violating a greater number of criteria appear to be decreased in this updated review. The validity criteria violated in the five trials meeting minimal design and protocol criteria here were, in order of frequency, IV (4 trials), SCV (2 trials), EV (2 trials), and CV (0). The latter probably is an underestimate due to our own specification for criterion violation, which accepts optimal pain measure sampling of the "pain construct" but does not require a multidimensional assessment of pain specifically mandating a combination of subjective, objective, and physiological pain measures in all trials. The issues concerning IV were related to controlling for impact of adverse event differences on blinding, placebo effects, effects of other prescribed medications that may have analgesic effects (e.g., benzodiazepines like oxazepam), type of pain syndrome, pain duration, and personality differences between groups. Issues concerning SCV involved mul-
tiple tests without citing an experiment-wide error rate and definition of pain outcome measures (Le., using the last week of the treatment period alone rather than the entire period). Issues involving EV included unusually long history of pain and unusually high prevalence of psychiatric disorders. Regarding the prior review,' the order of frequency (descending) of violation for 16 of 53 trials of these same criteria was SCV, IV, CV, and EV. Hence, it may be preliminarily concluded that more recent studies have improved somewhat in terms of attention to SCV and CV. However, the latter remains a source of concern, in that many studies still used predominantly subjective variables, though there was a better attempt to adequately describe the measures and cite appropriate sources for their reliability and validity than had been true in prior research. This, however, does not answer the remaining CV issue of a focus on subjective, self-report measures over more objective, rating measures (e.g., by blinded assessors with no other study duties). In addition, the focus on the subjective and objective domains occurs to the virtual exclu-
FOGUS/Goodkin et al.
243
Continued Trial Durationt (weeks) 6
12,
Efficacy of Pain Relief
Criteria Failed:/:
Decreased pain intensity (P < .02); no significant difference in activity nor analgesic intake
IV, EV
Though baseline differences were largely examined and controlled, no specific report of control for difference in personality variables; relatively high incidence of Axis I psychiatric disorders in sample; inclusion criteria regarding pain level unclear
NA
D
DVs of undemonstrated reliability and validity, no washout period; ? blind, as several side effects more frequent and persistent in desipramine group
NA
D
No true control group without active treatment; subjects not treated under blind conditions; medication protocol started at a dose where approximately 1/3 required dose reduction
NA
D, P
Protocol violated with 10 "completers" finishing only 1 of 3 weeks of treatment; 40% drop-out rate; ? blind, due to increased adverse events with amitriptyline (sedation; dry mouth); most DVs of questionable reliability and validity; no washout period
NA
D
No control group; ? blind, as different drugs had tablets of different shape and color and increased number and severity of adverse events with maprotiline; DVs largely subjective and of unestablished reliability and validity
NA
D
No true control group without active treatment; ? blind, due to side effect increase at 75 mg, though number of pills per day was controlled; no run-in period; subjects continued antidepressants during trial; unclear relation to prior study
6 on each drug 12
6,
3 weeks each condition
12,
5 on each drug
9,
Comments
3 three-week periods
sion of the physiological domain of pain measurement (e.g., nociceptive reflex threshold," physical activity by a computerized monitor," or allodynia"). A recommendation for future studies might still include, therefore, that DVs be selected that reflect these three domains of the "universe" of possible pain measures. Beyond the minimal design and protocol criteria described earlier, all of the validity criteria are important to the future planning of antidepressant trials for chronic, benign pain syndromes. The IV issues are of particular importance and are the most frequently violated of the validity criteria rated here. The violation of IV is directly relevant to the results of a trial, since IV refers to the evidence that there is a causal relationship between the antidepressant drug tested and the measurements of pain treatment response. Examples of violation of IV include the failure to control for other concurrent prescribed medications affecting pain; concurrent nonpharmacological treatments (e.g., neurosurgery, nerve blocks, transcutaneous electrical nerve stimulation units, cognitive behavioral therapy, behav-
ioral therapy, and other psychotherapy); as well as ongoing alcohol and recreational substance use in determining relation to outcome. In addition, threats to the blinding of a trial raise questions concerning IV, since knowledge of treatment assignment may then become an intervening variable biasing the direction of effects observed (exemplified by reference 12). The occurrence of significant placebo effects also represent a threat to IV, since the placebo effect itself becomes an intervening variable mediating the observable differences between treatment and "no treatment" groups (exemplified by reference 13). Numerous misconceptions exist regarding the placebo effect: about one third of patients will have a placebo effect in any clinical trial, the placebo effect is always brief, there is a placebo responder personality type, placebo responders have no primary pain disorder, and placebo administration is equivalent to no treatment." In reality, placebo response rates are quite variable (15-70% or more), placebo effects may last several years (e.g., in surgery trials), individuals tend not to be consistent
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about showing placebo response over placebo administrations, and placebo responses have definable pharmacokinetics as well as potential adverse effects (i.e., nocebo effects)." Placebo responses in antidepressant trials of chronic, benign pain syndromes are a particularly frequent problem. This is due .to the fact that many chronic, benign pain syndromes are intermittent by nature (e.g., chronic low back pain syndrome), many chronic pain subjects may seek out a trial when their pain is unusually severe (resulting in a problem of regression to the mean over the course of the trial), and pain subjects may be particularly liable to experience nonspecific treatment effects (e.g., such as those associated with provider warmth and interest as well as prestige of the treatment and setting). Another issue relevant to IV is that the type of pain syndrome examined may significantly impact the results of antidepressant drug treatment. This is particularly important in trials using samples with mixed types of chronic, benign pain syndromes.<,16,20,21,25,33 Although it had been previously concluded that trials of mixed chronic pain syndromes had decreased since 1983,' this review suggests that there has been a resurgence of such trials (35%). However, the prior rate of failure of minimal design and protocol criteria for such trials was 100%, whereas in this review it has decreased to 67%. Although it has been argued that such trials are specifically required to determine a syndrome-independent, analgesic effect of antidepressants," studies of mixed, chronic, benign pain syndromes are hampered by increased sample heterogeneity resulting in decreased statistical power. Finally, IV was affected here by lack of control for personality variables that may affect pain reports," baseline differences,"> mood disturbance (depression, anxiety, anger) within the normal ranqe," and psychiatric disorders." High drop-out rates (>40%)20 can also raise concern about trial IV due to bias related to protocol compliance factors. This IV concern can be significantly alleviated by the use of an "intention to treat" analysis." Consistent documentation of protocol compliance (e.g., by study drug8,20 and opioid analgesic pill counts," blood levels of study drug,8,12,15,16,18,19,25,30,33 and use of toxicology screens for alcohol and recreational substance use") would also substantiate IV and add to trial comparability in future studies. Documenting compliance with intake of other analqesic drugs can be helpful as well (e.g., non-narcotic [non-opioid] analgesics such as nonsteroidal anti-inflammatory drugs and benzodiazepines [oxazepam'<"] as either "no intake" or "continued intake at baseline levels throughout the trial"). In addition, statistical analyses can use controls for depression, opioid analgesic use, and litigation status defined as blocking factors in ANOVA.8 Testing the integrity of the blind by a report of a guess about treat-
ment assignment both by subject and evaluators can support the integrity of the blind and IV. Regarding SCV, improvements were noteworthy in the two most frequent violations in the area previously notedt-e-reliability of the DVs and report of the analyses in sufficient detail. However, several comments can again be made regarding the most commonly use subjective measure-the visual analog scale (VAS) for pain and other associated outcomes. Though previously? we had noted that VASs were rarely well specified, some improvement has occurred in this updated review in describing the VAS used in terms of absolute versus comparative type and calibration method. However, alternation of the poles of the scale to avoid response bias was not reported by any of these trials. Moreover, the use of a standardized instruction set and a training period for the subject to learn how to characterize his or her pain, for example, by acute and chronic components, in a reliable and valid manner were not discussed. In addition, scoring that optimally corrects for the high variability of this type of measure (e.g., slopes rather than means) received little attention. Such changes would further improve the SCV for VAS outcome variables in future trials. In addition, a greater focus remains to be established for other areas relevant to SCV. Important areas in this regard are proper methods of statistical analyses for repeated measures designs, methods appropriate to the measurement level of the variable, and the use of multiple significance tests without adjustment of the type I error rate. Nearly 50% (8/17) of the trials used a crossover design.'2,15,18-2,,30,32 For such designs repeated measures ANOVA takes advantage of the power inherent in using subjects as their own control, while allowing for a correction for period effects. The test for carryover effect in a twoperiod crossover and the clear lack of such an effect are prerequisites for a valid test of drug treatment effect. This analysis was properly used in interpretation of results in three of the eight crossover trials. '8,30,32 Another issue in evaluating SCV involves choice of statistical analysis where multiple outcome measures of pain are utilized. In a crossover design, where repeated measures ANOVA is indicated, consideration of multiple DVs should either use a corrected a or analysis of a composite index. In a non-crossover design, where repeated measure ANOVA mayor may not be advantageous and sample size is adequate, simultaneous analyses of multiple variables by MANOVA is preferable to multiple univariate analyses." Choice of statistical analyses appropriate to the measurement level of the outcome variable (Le., nominal, ordinal, interval, or ratio) can also be improved on. '3,15 Specifically, if outcome is measured on an interval or ratio scale, then parametric statistics are preferable, unless sample distribution
FOGUS/Goodkin et al.
anomalies preclude their use (e.g., deviations from normality or whatever other theoretical distribution is required by the statistical test used). Regarding EV, the scope of generalization that can be made beyond the specific sample, two trials are relevant here. 8 ,33 In one trial," EV was limited by the "superchronic" sample recruited, with a history of chronic low back pain syndrome of 20.3 years from the first reported episode. Site of recruitment was also a source of variance in this trial. However, both of these variables were controlled for in the statistical analyses conducted," Another study" raised concern about EV due to a high prevalence of psychiatric disorders (51%) in the sample. In general, more attention should be paid to issues relating to EV in future trials, for example, the influence of the sociodemographic characteristics of the particular subjects recruited, as well as the setting and conditions of the trial. Comparison of sociodemographic characteristics of dropouts versus completers and those enrolled versus those approached who refused enrollment can aid in the support of trial EV. For example, ethnicity is a relevant variable relating to cultural influences on pain reportinq." In conclusion, the use of antidepressant medication for analgesia in chronic pain syndrome patients has become a clinical nostrum in recent years. For example, a quick reference guide for clinicians on cancer pain states that antidepressants have "innate analgesic properties" and "are useful in pharmacological management of neuropathic pain" (also commonly seen in chronic, benign pain syndromes)." It is also stated that amitriptyline is the "tricyclic agent of choice" for this indication. Although prior reviews of antidepressant medication for chronic, benign pain syndromes concluded that the response rate averages 83% in this setting,' critical evaluation of the literature based on meta-analytic review has been reported only infrequently. Such reports have been consistent recently in suggesting that the antidepressant drugs may, indeed, have an analgesic effect (though this is disputed), but that the magnitude of the effects may be smaller than previously thought and appear to be quite modest,":" if present.'> In addition, there has been more recognition of the methodological limitations of published studies in metaanalytic reviews.7,23,27 One problem in this area is that there may be numerous unpublished trials with nonsignificant effect sizes-the "file drawer" problem. Statistical correction for this problem specifying a "fail safe N" has been published" and should be used in future meta-analyses. It must also be considered that, in many instances, comments cited in the Table and in our prior review' are based on the limitations of published reports imposed by journal reviewers and editors upon the investigators. Specific issues related to presentation of
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missing data, comparative analyses with those refusing enrollment, and detailed presentations of control variables are relevant in this regard. Such limitations should, perhaps, be reconsidered by journal reviewers and editorial boards. With the foregoing limitations acknowledged, this updated review of the analgesic efficacy of antidepressants for chronic, benign pain syndromes confirms that antidepressants cannot be concluded to be a generally effective treatment modality, although we previously have reported that they might be effective for headache.' Chronic low back pain syndrome has been examined specifically in several reviews, with negative conclusions about the analgesic efficacy of antidepressants.v"> Interestingly, depressed mood and decreased functional status, but not pain intensity, have been associated with somatic complaints in chronic low back pain syndrome patients. ' Given the above conclusion, what, then, might be the most appropriate clinical guidelines to set forth for prescribing antidepressant pharmacotherapy in chronic, benign pain syndrome patients? First, it should be emphasized that the treatment of chronic, benign pain syndromes (as with other chronic medical illnesses) is best proposed from the broad standpoint of a multidisciplinary framework involving the biological, psychodynamic, behavioral, sociocultural, and phenomenological determinants of pain complaints as well as other pain behaviors, as described by numerous investigators. 5,6,25,29 Within this broad scope of relevant intervention at these five levels, antidepressant pharmacotherapy is properly conceived as one possible intervention at the biological level. Once an intervention at the biological level has been included in the pain management plan following the thorough multidisciplinary investigation of the specific patient's needs, comparative interventions at this level then may be considered, depending on the specific pain syndrome involved (e.g., transcutaneous electrical nerve stimulation units, peripheral nerve blocks, trigger point injection, neurosurgery, physical therapy, and pharmacotherapy, including opioids, neuroleptics, anticonvulsants, psychostirriulants, and antidepressants). It may reasonably be stated that an indication for antidepressant pharmacotherapy is a coexisting psychiatric disorder responsive to such treatment (e.g., major depressive disorder)." It may also be concluded that headache pain (regardless of depressive disorder) should be considered an indication as we11. 7,17,23 Finally, chronic, benign pain syndromes associated with other disorders may be considered for antidepressant treatment, but only after the failure of all other treatment options accessible and indicated for the specific syndrome involved. This conclusion promulgates a more circumscribed role for the use of antidepressant pharmacotherapy than has been advocated generally. It has been suggested that this
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conclusion is "counter to the experience of most practitioners"." Though this has not invariably been found," this suggestion may, indeed, be true. Yet, the purpose of a clinical trial is to conduct a prospective study in which a treatment is compared to a control condition for the express purpose of differentiating -an experimentally valid observation from clinical observation, which is clearly subject to bias regardless of the breadth of its consensus. It has also been suggested that the "minimal" design and protocol criteria used here are simply too rigorous to require for entry into an efficacy analysis, especially after the validity criteria are superimposed. Yet psychopharmacological drug trials generally, and analgesic trials particularly, have been plagued by confounding variables of a wide variety of types-eoncomitant medications affecting pain, pain syndrome heterogeneity, high drop-out rates, and differential side effects, placebo response patterns, ethnic pain responses, and pain outcome measure scope and choices, to name several. Hence, we submit that criteria like those adopted here are necessary to achieve the goal of correctly inferring conclusions about the results of the current literature concerning the putative analgesic efficacy of antidepressant medication for chronic, benign pain syndromes. Therefore, it is with these caveats that we put forth the aforementioned clinical guidelines based upon the current state of knowledge.
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25. Pilowsky I, Barrow CG: A controlled study of psychotherapy and amitriptyline used individually and in combination in the treatment of chronic intractable, 'psychogenic' pain. Pain 40:3-19, 1990 26. Rosenthal R: Meta-analysis: a review. Psychosom Med 53:247-271, 1991 27. Turner JA, Denny MC: Do antidepressant medications relieve chronic low back pain? J Fam Pract 37: 545-553,1993 28. Turner JA, Deyo RA, Loeser JD, Von Korff M, Fordyce WE: The importance of placebo effects in pain treatment and research. JAMA271:1609-1614, 1994 29. Vrancken MAE: Schools of thought on pain. Section M. Soc Sci Med 29:435-444, 1989
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30. Watson CPN, Chipman M, Reed K, Evans RJ, Birkett N: Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial. Pain 48:2936, 1992 31. White K, Kando J, Park T, Waternaux C, Brown WA: Side effects and the "blindability" of clinical drug trials. Am J Psychiatry 149:1730-1731,1992 32. Ziegler OK, Hurwitz A, Hassanein RS et al: Migraine prophylaxis: a comparison of propranolol and amitriptyline Arch Neurol 44:486-489, 1987 33. Zitman FG, Linssen ACG, Edelbroek PM, Stijnen T: Low dose amitriptyline in chronic pain: the gain is modest. Pain 42:35-42, 1990