Ajay D. Wasan

Psychiatric History and Psychologic Adjustment as Risk Factors for Aberrant Drug-related Behavior Among Patients With Chronic Pain

ObjectiveTo investigate the role of psychiatric history and psychologic adjustment on aberrant drug-related behavior among patients prescribed opioids for noncancer pain. MethodsTwo hundred twenty-eight patients prescribed opioids for chronic pain were classified as either high or low on psychiatric morbidity on the basis of their responses on the psychiatric subscale of the Prescription Drug Use Questionnaire (PDUQ). They also completed the Brief Pain Inventory (BPI), Screener and Opioid Assessment for Pain Patients (SOAPP), and the Current Medication Misuse Measure (COMM). Patients were followed for 5 months and submitted a urine toxicology screen, and their treating physician completed the Prescription Opioid Therapy Questionnaire (POTQ). On the basis of the results from the SOAPP, COMM, POTQ, and urine screens, patients were classified as positive or negative on the Drug Misuse Index (DMI). ResultsOne hundred and three (N=103) of the patients (45%) were classified in the low psychiatric group (Low Psych) whereas 55% (N=125) were classified in the high psychiatric morbidity group (High Psych). High Psych patients were significantly younger than Low Psych patients and had been taking opioids longer (P<0.05). The High Psych group showed significantly higher SOAPP and COMM scores than the Low Psych patients (P<0.001), had a greater frequency of abnormal urine toxicology screens (P<0.01), and significantly higher scores on the DMI (P<0.001). A consistent association was found between psychiatric morbidity and prescription opioid misuse in chronic pain patients. DiscussionPsychiatric factors, such as a history of mood disorder, psychologic problems, and psychosocial stressors, may place patients at risk for misuse of prescription opioids. Future studies to elucidate the risk of medication misuse and aberrant drug behavior among this patient population are needed.

Urine toxicology screening among chronic pain patients on opioid therapy: frequency and predictability of abnormal findings.

ObjectiveTo examine the incidence of abnormal urine toxicology screening among chronic pain patients prescribed opioids for their pain and to relate these results to patient descriptors and type, number, and dose of prescribed opioids. MethodsA retrospective analysis of data from 470 patients who had urine screening at a pain management program in an urban teaching hospital was performed. Urine samples were analyzed using gas chromatography-mass spectrometry. Patients were categorized as having urine screens that were “normal” (expected findings based on their prescribed drugs) or abnormal. Abnormal findings were those of (1) absence of a prescribed opioid, (2) presence of an additional nonprescribed controlled substance, (3) detection of an illicit substance, and (4) an adulterated urine sample. ResultsForty-five percent of the patients were found to have abnormal urine screens. Twenty percent were categorized as having an illicit substance in their urine. Illicit substances and additional drugs were found more frequently in younger patients than in older patients (P<0.001). No other variables were found to predict abnormal urine screen results. DiscussionThese results confirm past findings that random urine toxicology screens among patients prescribed opioids for pain reveal a high incidence of abnormal findings. Common patient descriptors, and number, type, and dose of prescribed opioids were found to be poor predictors of abnormal results.

The association between negative affect and opioid analgesia in patients with discogenic low back pain

&NA; Comprised mainly of depression, anxiety, and high neuroticism, psychopathology diminishes the effectiveness of many chronic pain treatments. But, it is not known if it is associated with diminished opioid analgesia in patients with chronic, noncancer pain. We tested the hypothesis that psychopathology diminishes opioid analgesia in patients with discogenic low back pain in 60 patients not on opioids in a double blind, placebo controlled, random crossover designed trial. Patients were stratified into three groups of psychological symptom severity (LOW, MOD, and HIGH), based on composite scores on depression, anxiety for pain, and neuroticism scales. Subjects were given intravenous morphine (4–6 mg dosed by ideal body weight) and placebo in random order on separate visits, and completed serial pain ratings over three hours at each session. With 20 subjects per group, there were nonsignificant differences between groups in the distribution of age, gender, baseline pain (avg. 6.1/10), radicular pain, and morphine dose (5.0 mg). For morphine analgesia, using a total pain relief calculation (TOTPAR), the LOW group had 65.1% TOTPAR vs. 41.0% in the HIGH group, P=.026. For placebo analgesia the LOW group had 7.7% TOTPAR vs. 23.5% in the HIGH group, P=.03. A morphine minus placebo analgesia calculation revealed 59.2% TOTPAR in the LOW group vs. 21.7% in the HIGH group, P=.0001. High levels of psychopathology are associated with diminished opioid analgesia in patients with discogenic low back pain. These results have implications for the prescription of oral opioids to patients with chronic low back pain and psychopathology.

Evidence for brain glial activation in chronic pain patients

Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand (11)C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for (11)C-PBR28, nine patient-control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29-63 for patients and 28-65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions.

Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations

A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo (“assay sensitivity”). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence‐based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.

Substance misuse treatment for high-risk chronic pain patients on opioid therapy: A randomized trial

&NA; Chronic pain patients who show aberrant drug‐related behavior often are discontinued from treatment when they are noncompliant with their use of opioids for pain. The purpose of this study was to conduct a randomized trial in patients who were prescribed opioids for noncancer back pain and who showed risk potential for or demonstration of opioid misuse to see if close monitoring and cognitive behavioral substance misuse counseling could increase overall compliance with opioids. Forty‐two patients meeting criteria for high‐risk for opioid misuse were randomized to either standard control (High‐Risk Control; N = 21) or experimental compliance treatment consisting of monthly urine screens, compliance checklists, and individual and group motivational counseling (High‐Risk Experimental; N = 21). Twenty patients who met criteria indicating low potential for misuse were recruited to a low‐risk control group (Low‐Risk Control). Patients were followed for 6 months and completed pre‐ and post‐study questionnaires and monthly electronic diaries. Outcomes consisted of the percent with a positive Drug Misuse Index (DMI), which was a composite score of self‐reported drug misuse (Prescription Drug Use Questionnaire), physician‐reported abuse behavior (Addiction Behavior Checklist), and abnormal urine toxicology results. Significant differences were found between groups with 73.7% of the High‐Risk Control patients demonstrating positive scores on the DMI compared with 26.3% from the High‐Risk Experimental group and 25.0% from the Low‐Risk Controls (p < 0.05). The results of this study demonstrate support for the benefits of a brief behavioral intervention in the management of opioid compliance among chronic back pain patient at high‐risk for prescription opioid misuse.

Default mode network connectivity encodes clinical pain: an arterial spin labeling study.

Summary Patterns of intrinsic connectivity within the brain encode intensity of clinical pain and predict sustained pain in patients with chronic low back pain. Abstract Neuroimaging studies have suggested the presence of alterations in the anatomo‐functional properties of the brain of patients with chronic pain. However, investigation of the brain circuitry supporting the perception of clinical pain presents significant challenges, particularly when using traditional neuroimaging approaches. While potential neuroimaging markers for clinical pain have included resting brain connectivity, these cross‐sectional studies have not examined sensitivity to within‐subject exacerbation of pain. We used the dual regression probabilistic Independent Component Analysis approach to investigate resting‐state connectivity on arterial spin labeling data. Brain connectivity was compared between patients with chronic low back pain (cLBP) and healthy controls, before and after the performance of maneuvers aimed at exacerbating clinical pain levels in the patients. Our analyses identified multiple resting state networks, including the default mode network (DMN). At baseline, patients demonstrated stronger DMN connectivity to the pregenual anterior cingulate cortex (pgACC), left inferior parietal lobule, and right insula (rINS). Patients’ baseline clinical pain correlated positively with connectivity strength between the DMN and right insula (DMN–rINS). The performance of calibrated physical maneuvers induced changes in pain, which were paralleled by changes in DMN–rINS connectivity. Maneuvers also disrupted the DMN–pgACC connectivity, which at baseline was anticorrelated with pain. Finally, baseline DMN connectivity predicted maneuver‐induced changes in both pain and DMN–rINS connectivity. Our results support the use of arterial spin labeling to evaluate clinical pain, and the use of resting DMN connectivity as a potential neuroimaging biomarker for chronic pain perception.

Quantitative sensory testing and mapping a review of nonautomated quantitative methods for examination of the patient with neuropathic pain

ObjectivesDespite a growing interest in neuropathic pain, neurologists and pain specialists do not have a standard, validated, office examination for the evaluation of neuropathic pain signs to complement the neurologic, musculoskeletal, and general physical examinations. An office neuropathic pain examination focused on quantifying sensory features of neuropathic pain, ranging from deficits to allodynia and hyperalgesia, and evoked by a physiologically representative array of stimuli, will be an essential tool to monitor treatment effectiveness and for clinical investigation into the mechanisms and management of neuropathic pain. Such an examination should include mapping of areas of stimulus-evoked neuropathic pain and standardized, reproducible quantitative sensory testing (QST) of tactile, punctuate, pressure, and thermal modalities. MethodsWe review quantitative sensory testing methodology in general and specific tests for the evaluation of neuropathic pain phenomena. ResultsNumerous quantitative sensory testing techniques for dynamic mechanical, pressure, vibration, and thermal sensory testing and mapping have been described. We propose a comprehensive neuropathic pain evaluation protocol that is based upon these available techniques. ConclusionsA comprehensive neuropathic pain evaluation protocol is essential for further advancement of clinical research in neuropathic pain. A protocol that uses tools readily available in clinical practice, when established and validated, can be used widely and thus accelerate data collection for clinical research and increase clinical awareness of the features of neuropathic pain.

Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations

Abstract Terminology related to prescription drug misuse and abuse is inconsistently defined. An expert panel developed consensus classifications and definitions for use in clinical trials. Abstract As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public–private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment’s abuse potential.

The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study.

IntroductionDespite recent advances in anti-inflammatory therapy, rheumatoid arthritis (RA) patients continue to rate pain as a priority. The etiology of RA pain is likely multifactorial, including both inflammatory and non-inflammatory components. In this study, we examine the association between disease activity, sleep, psychiatric distress and pain sensitivity in RA.MethodsFifty-nine female RA patients completed questionnaires and underwent pressure pain threshold testing to assess hyperalgesia/allodynia at joint and non-joint sites. Blood samples were taken to measure C-reactive protein (CRP). The association between disease activity, sleep problems, psychiatric distress and pain threshold was assessed using Pearson/Spearman correlations and multivariable linear regression. Disease activity levels, sleep problems and psychiatric distress were compared between RA patients with fibromyalgia and RA patients without fibromyalgia.ResultsIn unadjusted analyses, CRP was not correlated with pain threshold, but tender joint count was inversely correlated with pain threshold at all sites (P ≤ 0.004). Sleep problems were associated with low pain threshold at all sites (P ≤ 0.0008). Psychiatric distress was associated with low pain threshold at the wrist and thumbnail (P ≤ 0.006). In multivariable linear regression models, CRP was inversely associated with wrist pain threshold (P = 0.003). Sleep problems were inversely associated with pain threshold at all sites (P ≤ 0.01), but psychiatric distress was not. Despite differences in pain threshold, CRP levels and sleep problems between RA patients with fibromyalgia and those without fibromyalgia, associations between these variables did not change when patients with fibromyalgia were excluded.ConclusionsMultivariable models are essential in analyses of pain. Among RA patients, inflammation is associated with heightened pain sensitivity at joints. In contrast, poor sleep is associated with diffuse pain sensitivity, as noted in central pain conditions such as fibromyalgia. Future studies examining pain sensitivity at joint and non-joint sites may identify patients with different underlying pain mechanisms and suggest alternative approaches to treating RA pain.