Denying the Truth Does Not Change the Facts: A Systematic Analysis of Pseudoscientific Denial of Complex Regional Pain Syndrome.

PURPOSE: Several articles have claimed that complex regional pain syndrome (CRPS) does not exist. Although a minority view, it is important to understand the arguments presented in these articles. We conducted a systematic literature search to evaluate the methodological quality of articles that claim CRPS does not exist. We then examined and refuted the arguments supporting this claim using up-to-date scientific literature on CRPS. METHODS: A systematic search was conducted in MEDLINE, EMBASE and Cochrane CENTRAL databases. Inclusion criteria for articles were (a) a claim made that CRPS does not exist or that CRPS is not a distinct diagnostic entity and (b) support of these claims with subsequent argument(s). The methodological quality of articles was assessed if possible. RESULTS: Nine articles were included for analysis: 4 narrative reviews, 2 personal views, 1 letter, 1 editorial and 1 case report. Seven points of controversy were used in these articles to argue that CRPS does not exist: 1) disagreement with the label "CRPS"; 2) the "unclear" pathophysiology; 3) the validity of the diagnostic criteria; 4) CRPS as a normal consequence of immobilization; 5) the role of psychological factors; 6) other identifiable causes for CRPS symptoms; and 7) the methodological quality of CRPS research. CONCLUSION: The level of evidence for the claim that CRPS does not exist is very weak. Published accounts concluding that CRPS does not exist, in the absence of primary evidence to underpin them, can harm patients by encouraging dismissal of patients' signs and symptoms.

Executive functions in aphasia: A novel aphasia screening for cognitive flexibility in everyday communication.

Besides language deficits, persons with aphasia can present with impairments in executive functions such as cognitive flexibility. Since these impairments can restrict communicative abilities, diagnostics for aphasia should include their assessment. However, tests of executive functions, including symptoms expressed in everyday communication, are lacking for aphasia. Thus, our aim was to fill this gap and study the basic psychometric properties of the novel Cognitive Flexibility in Aphasia Screening. For a pilot evaluation, 26 German patients were examined with tests for language and cognitive flexibility as well as the novel screening. Moreover, 20 non-aphasic persons conducted the latter. We performed a Receiver Operating Characteristic analysis to investigate specificity and sensitivity, and multidimensional scaling to examine similarities between the screening and language/cognitive skills. We found good specificity and sensitivity and showed that the screening is correlated with language skills and verbal cognitive flexibility, revealing promising construct validity and feasibility of the new screening.

What do plasma beta-endorphin levels reveal about endogenous opioid analgesic function?

Plasma levels of beta-endorphin (BE), an endogenous opioid analgesic, are often reported as they relate to acute and chronic pain outcomes. However, little is known about what resting plasma BE levels might reveal about functioning of the endogenous opioid antinociceptive system. This study directly examined associations between resting plasma BE and subsequent endogenous opioid analgesic responses to acute pain in 39 healthy controls and 37 individuals with chronic low back pain (LBP). Resting baseline levels of plasma BE were assessed. Next, participants received opioid blockade (8 mg naloxone i.v.) or placebo in a double-blind, randomized, crossover design. Participants then underwent two acute pain stimuli: finger pressure (FP) pain and ischaemic (ISC) forearm pain. Blockade effects (naloxone minus placebo pain ratings) were derived to index endogenous opioid analgesic function. In placebo condition analyses for both pain stimuli, higher resting BE levels were associated with subsequently greater reported pain intensity (p's < 0.05), with this effect occurring primarily in healthy controls (BE × Participant Type interactions, p's < 0.05). In blockade effect analyses across both pain tasks, higher resting plasma BE predicted less subsequent endogenous opioid analgesia (smaller blockade effects; p's < 0.05). For the ISC task, these links were significantly more prominent in LBP participants (BE × Participant Type Interactions, p's < 0.05). Results suggest that elevated resting plasma BE may be a potential biomarker for reduced endogenous opioid analgesic capacity, particularly among individuals with chronic pain. Potential clinical implications are discussed.

Cognitive factors influence outcome following multidisciplinary chronic pain treatment: a replication and extension of a cross-lagged panel analysis.

Reducing maladaptive cognitions is hypothesized to constitute an active therapeutic process in multidisciplinary pain programs featuring cognitive-behavioral interventions. A cross-lagged panel design was used to determine whether: a) early-treatment cognitive changes predicted late-treatment pain, interference, activity and mood changes, but not vice versa; b) three cognitive factors made unique contributions to outcome; c) substantial cognitive changes preceded substantial improvements in outcome. Sixty-five chronic pain patients, participating in a 4-week multidisciplinary program, completed measures of pain helplessness, catastrophizing, pain-related anxiety (process factors), pain severity, interference, activity level and depression (outcomes) at pre-, mid- and posttreatment. Results showed that early-treatment reductions in pain helplessness predicted late-treatment decreases in pain and interference, but not vice versa, and that early-treatment reductions in catastrophizing and pain-related anxiety predicted late-treatment improvements in pain severity, but not vice versa. Findings suggested that the three process factors predicted improvements mostly in common. However, little evidence was found that large early-treatment reductions in process variables preceded extensive improvements in pain. Findings replicate those of a recent report regarding cross-lagged effects, and offer support that cognitive changes may indeed influence late-treatment changes in outcomes.

A fourth empirically derived cluster of chronic pain patients based on the multidimensional pain inventory: evidence for repression within the dysfunctional group.

The authors proposed that chronic pain patients with repressive defenses are not represented in current 3-cluster solutions of the Multidimensional Pain Inventory (MPI; R. D. Kerns, D. C. Turk, & T. E. Rudy, 1985) and that such a group can be distinguished by using a measure of defensiveness together with subscales of the MPI. They expected these patients to be described both by high defensiveness and by elevated pain and disability but minimal emotional distress. For 178 pain patients, hierarchical cluster analyses were performed on the MPI and Balanced Inventory of Desirable Responding (D. L. Paulhus, 1984). A 3-cluster solution replicated past findings in identifying dysfunctional, interpersonally distressed, and adaptive coper groups. A 4-cluster solution fit the data better, with a repressor group described by high pain, low activity and low distress emerging from the dysfunctional group. Profile analysis of validation measures showed that repressors scored comparably with dysfunctional patients on somatic symptoms of depression, pain severity, and perceived disability but significantly higher on these factors than the adaptive copers. Repressors scored comparably with adaptive copers on cognitive-affective symptoms of depression, anxiety, and anger but significantly lower on these variables than dysfunctional patients. Repressors also reported greater pain severity and perceived disability relative to their reports of negative affect, whereas dysfunctional and adaptive coper groups exhibited no such disparities. Without a measure of defensiveness, the MPI may misclassify a distinct group of patients as dysfunctional, but who readily endorse physical symptoms yet report low levels of emotional distress.

Conducting clinical trials to establish drug efficacy in chronic pain.

Design of clinical trials to establish drug efficacy in chronic pain is a complicated issue, and numerous factors must be considered in identifying an optimal study design. Investigators should begin by identifying a focused and testable research question, with the outcome variables operationalized in a way that allows appropriate quantitative analysis. The prospective, randomized, placebo-controlled, doubled-blind study using validated quantitative measures is considered the optimal clinical trial design. Within this general study type, the between-subjects design has less statistical power than does the crossover design, in which the patient serves as his or her own control. However, potential problems with the drug effects from the first condition carrying over into, and confounding, the second drug condition present a noteworthy limitation that must be addressed through adequate washout periods and statistical control if crossover designs are used. Retrospective designs may be useful primarily to take advantage of samples of convenience for development of pilot data that provide the basis for conducting better-controlled prospective studies. Sample selection issues must be considered during study design, including the sample size required (based on statistical power analysis), appropriate inclusion and exclusion criteria, and likely availability of qualifying patients. There are numerous statistical options for analyzing data that must be selected based on whether data are parametric or nonparametric, whether within-subject (crossover) or between-subject comparisons are used, and whether baseline values of outcome measures affect the degree of change in these measures over the course of the study. Involvement of a biostatistical consultant is recommended during all phases of clinical trials.

An examination of the psychometric structure of the Multidimensional Pain Inventory.

Factor analyses to create the Multidimensional Pain Inventory (MPI) warrant further examination due to small sample size, the use of separate factor analyses for each MPI section, and lack of evidence for the replicability of the factor model. The present study randomly assigned 972 respondents to one of three samples. Study 1 used data from Sample 1 (n = 452) to examine the replicability of the MPI factor structure reported by Kerns, Turk, and Rudy (1985), and to measure the internal consistencies of MPI scales. In Study 2, confirmatory factor analyses using Sample 2 data (n = 267) verified a revised MPI factor structure that was generated in Study 1; cross-validation was achieved using data from Sample 3 (n = 253). The revised MPI model differed from the original model in its number of scales and pattern of scale loadings. Recommendations for the refinement of the MPI are proposed.

Signs and symptoms of the myofascial pain syndrome: a national survey of pain management providers.

OBJECTIVE: The goal of this study was to assess clinical consensus regarding whether myofascial pain syndrome (MPS) is a legitimate and distinct diagnosis as well as the signs and symptoms characterizing MPS. DESIGN: A standardized mailed survey with return postage provided. SUBJECTS: A total of 1,663 American Pain Society members in medically related disciplines listed in the 1996/1997 directory. OUTCOME MEASURES: A standardized survey assessing clinical opinion regarding whether MPS is a legitimate diagnosis, whether MPS is a clinical entity distinct from fibromyalgia, and the signs and symptoms believed to be "essential to," "associated with," or "irrelevant to" to the diagnosis of MPS. RESULTS: Of the 403 surveys returned, 88.5% respondents reported that MPS was a legitimate diagnosis, with 81% describing MPS as distinct from fibromyalgia. The only signs and symptoms described as essential to the diagnosis of MPS by greater than 50% of the sample were regional location, presence of trigger points, and a normal neurologic examination. Regarding the signs and symptoms considered to be essential or associated with MPS, more than 80% of respondents agreed on regional location, trigger points, normal neurologic examination, reduced pain with local anesthetic or "spray and stretch," taut bands, tender points, palpable nodules, muscle ropiness, decreased range of motion, pain exacerbated by stress, and regional pain described as "dull," "achy," or "deep." Sensory or reflex abnormalities, scar tissue, and most test results were considered to be irrelevant to the diagnosis of MPS by a large proportion of the respondents. CONCLUSIONS: There was general agreement across specialties that MPS is a legitimate diagnosis distinct from fibromyalgia. There was a high level of agreement regarding the signs and symptoms essential or associated with a diagnosis of MPS. Differences across specialties are discussed. This survey provides a first step toward the development of consensus-based diagnostic criteria for MPS, which can then be validated empirically.

Theoretical review: altered pain regulatory systems in chronic pain.

This review synthesizes the existing literature regarding the relationship between resting blood pressure and pain sensitivity, and the literature indicating possible endogenous opioid dysfunction in chronic pain. Adaptive interactions between the cardiovascular and pain regulatory systems occur in healthy individuals, with greater blood pressure associated with decreased acute pain sensitivity. Endogenous opioids appear necessary for full expression of this relationship. There is ample evidence indicating diminished endogenous opioid CSF/plasma levels in chronic pain patients, yet little is known about the functional effects of these opioid changes. A theoretical model is proposed based upon the literature reviewed suggesting progressive dysfunction in endogenous opioid systems with increasing chronic pain duration. This dysfunction is hypothesized to result in dysregulation of normally adaptive relationships between the cardiovascular and pain regulatory systems, resulting in increased chronic pain intensity and increased acute pain sensitivity among chronic pain patients. Preliminary data are consistent with the hypothesis of progressive opioid changes resulting in dysfunctional alterations in the adaptive blood pressure-pain relationship. Clinical implications of this theory are discussed.

Complex regional pain syndrome: are the IASP diagnostic criteria valid and sufficiently comprehensive?

This is a multisite study examining the internal validity and comprehensiveness of the International Association for the Study of Pain (IASP) diagnostic criteria for Complex Regional Pain Syndrome (CRPS). A standardized sign/symptom checklist was used in patient evaluations to obtain data on CRPS-related signs and symptoms in a series of 123 patients meeting IASP criteria for CRPS. Principal components factor analysis (PCA) was used to detect statistical groupings of signs/symptoms (factors). CRPS signs and symptoms grouped together statistically in a manner somewhat different than in current IASP/CRPS criteria. As in current criteria, a separate pain/sensation criterion was supported. However, unlike in current criteria, PCA indicated that vasomotor symptoms form a factor distinct from a sudomotor/edema factor. Changes in range of motion, motor dysfunction, and trophic changes, which are not included in the IASP criteria, formed a distinct fourth factor. Scores on the pain/sensation factor correlated positively with pain duration (P<0. 001), but there was a negative correlation between the sudomotor/edema factor scores and pain duration (P<0.05). The motor/trophic factor predicted positive responses to sympathetic block (P<0.05). These results suggest that the internal validity of the IASP/CRPS criteria could be improved by separating vasomotor signs/symptoms (e.g. temperature and skin color asymmetry) from those reflecting sudomotor dysfunction (e.g. sweating changes) and edema. Results also indicate motor and trophic changes may be an important and distinct component of CRPS which is not currently incorporated in the IASP criteria. An experimental revision of CRPS diagnostic criteria for research purposes is proposed. Implications for diagnostic sensitivity and specificity are discussed.

External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain.

Recent work in our research consortium has raised internal validity concerns regarding the current IASP criteria for Complex Regional Pain Syndrome (CRPS), suggesting problems with inadequate sensitivity and specificity. The current study explored the external validity of these IASP criteria for CRPS. A standardized evaluation of signs and symptoms of CRPS was conducted by study physicians in 117 patients meeting IASP criteria for CRPS, and 43 patients experiencing neuropathic pain with established non-CRPS etiology (e.g. diabetic neuropathy, post-herpetic neuralgia). Multiple discriminant function analyses were used to test the ability of the IASP diagnostic criteria and decision rules, as well as proposed research modifications of these criteria, to discriminate between CRPS patients and those experiencing non-CRPS neuropathic pain. Current IASP criteria and decision rules (e.g. signs or symptoms of edema, or color changes or sweating changes satisfy criterion 3) discriminated significantly between groups (P < 0.001). However, although sensitivity was quite high (0.98), specificity was poor (0.36), and a positive diagnosis of CRPS was likely to be correct in as few as 40% of cases. Empirically-based research modifications to the criteria, which are more comprehensive and require presence of signs and symptoms, were also tested. These modified criteria were also able to discriminate significantly, between the CRPS and non-CRPS groups (P < 0.001). A decision rule, requiring at least two sign categories and four symptom categories to be positive optimized diagnostic efficiency, with a diagnosis of CRPS likely to be accurate in up to 84% of cases, and a diagnosis of non-CRPS neuropathic pain likely to be accurate in up to 88% of cases. These results indicate that the current IASP criteria for CRPS have inadequate specificity and are likely to lead to overdiagnosis. Proposed modifications to these criteria substantially improve their external validity and merit further evaluation.

An examination of the validity of the IHS classification system for migraine and tension-type headache in the college student population.

The validity of the International Headache Society (IHS) classification system for college-aged students with headache was examined using cluster analysis. Undergraduate college student volunteers (N = 369) underwent a structured diagnostic interview for headaches, and the sample was divided into two subsamples for purposes of replication. A hierarchical cluster analysis (Ward's method) of the headache characteristics reported by the first subsample suggested a statistically distinct three-cluster solution, and the solution was replicated using the second subsample. It appeared that one cluster was tensionlike, while the other two were migrainelike. Nonhierarchical cluster analyses (K-means) of the cases from each subsample revealed a similar pattern of a tensionlike and two migrainelike clusters. Identical three-cluster solutions were found for the second subsample both by using cluster centers from the first subsample and by clustering the cases independently, suggesting that the cluster solution was not a random finding. The IHS classification system appears to lack adequate specificity and sensitivity for college-aged students with headache who report migrainelike symptoms. Thus, the generalizability of research results using college-aged students with headache to the adult population may be questionable.

Use of cluster analysis to validate IHS diagnostic criteria for migraine and tension-type headache.

Cluster analysis was used to validate headache diagnostic criteria of the International Headache Society (IHS). Structured diagnostic interviews were conducted on 443 headache sufferers from a community sample, which was randomly split to allow replication. Hierarchical cluster analysis of symptoms in both subsamples revealed two distinct (P<.001) clusters: (1) unilateral pulsating pain, pain aggravated by activity, and photophobia and phonophobia, and (2) bilateral pressing/tightening pain, mild to moderate intensity, and absence of nausea/vomiting. These clusters were consistent with IHS migraine and tension-type classifications, respectively. Replication using a non-hierarchical clustering technique, k-means cluster analysis, revealed a migrainelike patient cluster, reflecting more frequent pulsating, unilateral pain; more severe pain; and pain aggravated by activity; nausea, vomiting, photophobia, and phonophobia. A tensionlike patient cluster was also identified, reflecting more frequent pressing/tightening pain, mild to moderate pain, bilateral location, and absence of nausea/vomiting. These patient clusters were consistent across subsamples. International Headache Society diagnoses corresponded with classification based upon statistically derived clusters (P<.001). These results indicate that headache symptoms cluster empirically in a manner consistent with IHS criteria for migraine and tension-type headaches. Criterion overlap problems regarding pain intensity and duration were identified. Overall, these data support migraine and tension-type headache as distinct entities, and provide support for the IHS diagnostic criteria with minor modifications.

Endogenous opioids inhibit ambulatory blood pressure during naturally occurring stress.

OBJECTIVE: Laboratory experiments suggest that endogenous opioids inhibit blood pressure responses during psychological stress. Moreover, there seem to be considerable individual differences in the efficacy of opioid blood pressure inhibition, and these differences may be involved in the expression of risk for cardiovascular disease. To further evaluate the possible role of opioid mechanisms in cardiovascular control, the present study sought to document the effects of the long-lasting oral opioid antagonist naltrexone (ReVia, DuPont, Wilmington, DE) on ambulatory blood pressure responses during naturally occurring stress. METHOD: Thirty male volunteers participated in a laboratory stress study using naltrexone followed by ambulatory blood pressure under placebo and during the subsequent 24-hour period. Within-subject analyses were performed on ambulatory blood pressures under placebo and naltrexone conditions. RESULTS: Laboratory results indicate no significant group effects of naltrexone on blood pressure levels or reactivity. Ambulatory results indicate that during periods of low self-reported stress, no effect of opioid blockade was apparent. In contrast, during periods of high stress, opioid blockade increased ambulatory blood pressure. CONCLUSIONS: These findings suggest that naltrexone-sensitive opioid mechanisms inhibit ambulatory blood pressure responses during naturally occurring stress.

IASP diagnostic criteria for complex regional pain syndrome: a preliminary empirical validation study. International Association for the Study of Pain.

OBJECTIVE: To assess the ability of the International Association for the Study of Pain Complex Regional Pain Syndrome (CRPS) diagnostic criteria and associated features to discriminate between CRPS patients and patients with painful diabetic neuropathy. DESIGN: Prospective assessment of signs and symptoms in a series of CRPS and diabetic neuropathy patients. SETTING: University of Washington Multidisciplinary Pain Center. PATIENTS: A consecutive series of 18 CRPS patients and 30 diabetic neuropathy patients. INTERVENTIONS: Patients completed a 10-item patient history questionnaire assessing symptoms of CRPS prior to medical evaluation. The evaluating physician completed a 10-item patient examination questionnaire assessing objective signs of CRPS. OUTCOME MEASURES: The analyses conducted were designed to test the ability of CRPS signs and symptoms and associated features to discriminate between CRPS patients and diabetic neuropathy patients. RESULTS: Data analysis suggested that CRPS decision rules may lead to overdiagnosis of the disorder. Diagnosis based on self-reported symptoms can be diagnostically useful in some circumstances. The addition of trophic tissue changes, range of motion changes, and "burning" quality of pain did not improve diagnostic accuracy, but the addition of motor neglect signs did. Test of a CRPS scoring system resulted in improved accuracy relative to current criteria and decision rules. CONCLUSIONS: Poorly understood disorders lacking prototypical signs/symptoms and diagnostic laboratory testing must rely on the development of reliable diagnostic guidelines. The results of this study should assist in the further refinement of the CRPS diagnostic criteria.

Altered cardiovascular/pain regulatory relationships in chronic pain.

In healthy individuals, there is an inverse relationship between resting blood pressure (BP) and pain sensitivity. This study examined possible dysregulation of this adaptive relation in chronic pain patients, and tested whether the extent of this dysregulation is a function of pain duration. Continuous resting BP's were assessed for 5 min after a 5-min rest period in 121 chronic benign pain patients. Unlike the inverse relationship observed previously in normals, mean resting diastolic. BPs during the assessment period were correlated positively with ratings of pain severity. A Pain Duration x Systolic BP interaction emerged (p < .05) such that the magnitude of the BP-pain relation was greatest in patients with the longest duration of pain, r(38) = .50, p < .001. A hypothesized progressive alteration in endogenous pain regulatory systems in chronic pain patients was supported. A possible role of endogenous opioid dysfunction in accounting for these alterations is discussed.

Pain, psychological status, and functional recovery in chronic pain patients on daily opioids: a case comparison.

Long-term opioid therapy for chronic benign pain remains controversial. Most studies on the effectiveness of such regimens have been case series or case comparisons and very few randomized placebo-controlled studies are available. Overall, this research has produced mixed results. The current study sought to further explore issues regarding the effectiveness of opioids for chronic pain and to examine the use of adjunctive medications in these patients. A random sample of 100 patients taking daily opioids (Opioid) and 100 taking no opioids (Non-opioid) at evaluation were selected from the patient population of a tertiary care multidisciplinary pain program. Statistical analyses revealed that the two groups did not differ regarding pain type, duration, location, or surgical history. Non-Caucasians were less likely to be taking opioids than Caucasians (p<0.05). Relative to the Non-opioid group, Opioid patients were less frequently taking non-steroidal anti-inflammatories (p<0.01) and were more often taking anxiolytics (p<0.05) and muscle relaxants (p<0.01). Opioid patients reported higher (p<0.05) current pain and more frequently (p<0.05) reported current or past clinical depression or anxiety. No other significant differences were noted on measures of pain, psychological status, or functioning. Statistical removal of the effects of pain differences did not alter the pattern of results for psychological and functional measures. Although the study design employed did not allow determination of causality, it is consistent with previous work which has failed to reveal any advantage to use of daily opioids in the chronic pain population with regard to analgesia, decreased adjunctive medication use, or functional recovery. Well-designed, prospective, randomized studies are needed, but the current results suggest continued caution in the use of daily opioids until such studies become available.

Validation of thermography in the diagnosis of reflex sympathetic dystrophy.

OBJECTIVES: To examine the validity of several thermogram-derived indices of autonomic functioning in the diagnosis of reflex sympathetic dystrophy (RSD). DESIGN: A series of chronic pain patients were classified diagnostically based on thermogram results using discriminant function analysis, and validity measures (e.g., sensitivity, specificity) were used to determine the accuracy of computerized thermographic pixel analysis in discriminating RSD from other pathology. SETTING: The study was conducted at the Rush Pain Center, a multidisciplinary outpatient pain clinic. PATIENTS: A series of 46 chronic pain patients referred for suspected sympathetically mediated pain. INTERVENTIONS: All patients underwent computerized thermographic examination under a baseline condition after acclimating to a climate-controlled room, immediately after a cold challenge was applied to the contralateral uninvolved extremity (4 degrees C for 90 s) and 20 min after the cold challenge. OUTCOME MEASURES: Temperature during the three experimental periods, degree of temperature asymmetry between affected and nonaffected limbs during the three periods, response to cold challenge, and recovery following cold challenge were measured. RESULTS: Temperature asymmetry accurately discriminated between RSD and non-RSD patients, with the most accurate asymmetry measures obtained at baseline. Responses to cold challenge and actual temperature values did not discriminate between RSD and non-RSD pain patients. CONCLUSIONS: Thermography can be a useful component of RSD diagnosis. In situations where sensitivity and specificity are equally important, an asymmetry cutoff of 0.6 degree C appears optimal. If specificity (i.e., accurately ruling out non-RSD cases) is more important, a cutoff of 0.8 degree C or 1.0 degree C may be considered as well.