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Currently-used assessments for fibromyalgia require clinicians to suspect a fibromyalgia diagnosis, a process susceptible to unintentional bias. Automated assessments of standard patient-reported outcomes (PROs) could be used to prompt formal assessments, potentially reducing bias. We sought to determine whether hierarchical clustering of patient-reported pain distribution on digital body map drawings predicted fibromyalgia diagnosis. Using an observational cohort from the University of Pittsburgh's Patient Outcomes Repository for Treatment registry, which contains PROs and electronic medical record data from 21,423 patients (March 17, 2016-June 25, 2019) presenting to pain management clinics, we tested the hypothesis that hierarchical clustering subgroup was associated with fibromyalgia diagnosis, as determined by ICD-10 code. Logistic regression revealed a significant relationship between the body map cluster subgroup and fibromyalgia diagnosis. The cluster subgroup with the most body areas selected was the most likely to receive a diagnosis of fibromyalgia when controlling for age, gender, anxiety, and depression. Despite this, more than two-thirds of patients in this cluster lacked a clinical fibromyalgia diagnosis. In an exploratory analysis to better understand this apparent underdiagnosis, we developed and applied proxies of fibromyalgia diagnostic criteria. We found that proxy diagnoses were more common than ICD-10 diagnoses, which may be due to less frequent clinical fibromyalgia diagnosis in men. Overall, we find evidence of fibromyalgia underdiagnosis, likely due to gender bias. Coupling PROs that take seconds to complete, such as a digital pain body map, with machine learning is a promising strategy to reduce bias in fibromyalgia diagnosis and improve patient outcomes. PERSPECTIVE: This investigation applies hierarchical clustering to patient-reported, digital pain body maps, finding an association between body map responses and clinical fibromyalgia diagnosis. Rapid, computer-assisted interpretation of pain body maps would be clinically useful in prompting more detailed assessments for fibromyalgia, potentially reducing gender bias., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Variability in pain-related outcomes can hamper assay sensitivity of chronic pain clinical trials. Expectations of outcome in such trials may account for some of this variability, and thereby impede development of novel pain treatments. Measurement of participants' expectations prior to initiating study treatment (active or placebo) is infrequent, variable, and often unvalidated. Efforts to optimize and standardize measurement, analysis, and management of expectations are needed. In this Focus Article, we provide an overview of research findings on the relationship between baseline expectations and pain-related outcomes in clinical trials of pharmacological and nonpharmacological pain treatments. We highlight the potential benefit of adjusting for participants' expectations in clinical trial analyses and draw on findings from patient interviews to discuss critical issues related to measurement of expectations. We conclude with suggestions regarding future studies focused on better understanding the utility of incorporating these measures into clinical trial analyses. PERSPECTIVE: This focus article provides an overview of the relationship between participants' baseline expectations and pain-related outcomes in the setting of clinical trials of chronic pain treatments. Systematic research focused on the measurement of expectations and the impact of adjusting for expectations in clinical trial analyses may improve assay sensitivity., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (ie, "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (ie, targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of prespecified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: 1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, 2) designing clinical trials that can identify treatment-by-phenotype interactions, and 3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry., (Copyright © 2020. Published by Elsevier Inc.)

In health and disease, the somatosensory system has been interrogated with standardized research techniques, collectively referred to as quantitative sensory testing (QST). In neuropathic pain, QST has been used to characterize multiple sensory derangements. However, the use of QST outside the lab has been limited by several factors, including a lack of standardization, variability in procedural technique, and duration of testing that would be unacceptable for clinic. To address these shortcomings, the Neuropathic Pain Research Consortium designed an easy and low-cost "bedside" QST procedure. To test the hypothesis that this procedure would be clinically reliable over time and across different examiners, a multisite, blinded study was performed in subjects with postherpetic neuralgia. Generally, agreement between 2 examiners and over 2 study visits with 1 examiner was high. Additionally, intraclass correlation coefficients and Kappa statistics calculated showed that the battery of QST tests included were highly reliable. Interestingly, mechanical modalities (light brush, pinprick, pressure, and vibration) showed the highest reliability. The least reliable modalities were cool (room temperature) and warmth (38°C). These data demonstrate that the Neuropathic Pain Research Consortium beside QST protocol is reliable across examiner and over time, providing a validated QST tool for use in clinical practice and clinical trials. PERSPECTIVE: This blinded, multicenter trial in 32 patients with postherpetic neuralgia demonstrates bedside QST is reliable and suitable as a clinical trial outcome. The novel bedside battery could be used in clinical trials or in clinical practice over time given the reliability data presented in this article., (Copyright © 2019 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Placebo treatments and healing rituals share much in common, such as the effects of expectancy, and have been used since the beginning of human history to treat pain. Previous mechanistic neuroimaging studies investigating the effects of expectancy on placebo analgesia have used young, healthy volunteers. Using functional magnetic resonance imaging (fMRI), we aimed to investigate the neural mechanisms by which expectancy evokes analgesia in older adults living with a chronic pain disorder and determine whether there are interactions with active treatment. In this fMRI study, we investigated the brain networks underlying expectancy in participants with chronic pain due to knee osteoarthritis (OA) after verum (genuine) and sham electroacupuncture treatment before and after experiencing calibrated experimental heat pain using a well tested expectancy manipulation model. We found that expectancy significantly and similarly modulates the pain experience in knee OA patients in both verum (n = 21, 11 female; mean ± SD age 57 ± 7 years) and sham (n = 22, 15 female; mean ± SD age 59 ± 7 years) acupuncture treatment groups. However, there were different patterns of changes in fMRI indices of brain activity associated with verum and sham treatment modalities specifically in the lateral prefrontal cortex. We also found that continuous electroacupuncture in knee OA patients can evoke significant regional coherence decreases in pain associated brain regions. Our results suggest that expectancy modulates the experience of pain in knee OA patients but may work through different pathways depending on the treatment modality and, we speculate, on pathophysiological states of the participants., Perspective: To investigate the neural mechanisms underlying pain modulation, we used an expectancy manipulation model and fMRI to study response to heat pain stimuli before and after verum or sham acupuncture treatment in chronic pain patients. Both relieve pain and each is each associated with a distinct pattern of brain activation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Accurate assessment of inappropriate medication use events (ie, misuse, abuse, and related events) occurring in clinical trials is an important component in evaluating a medication's abuse potential. A meeting was convened to review all instruments measuring such events in clinical trials according to previously published standardized terminology and definitions. Only 2 approaches have been reported that are specifically designed to identify and classify misuse, abuse, and related events occurring in clinical trials, rather than to measure an individual's risk of using a medication inappropriately: the Self-Reported Misuse, Abuse, and Diversion (SR-MAD) instrument and the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS). The conceptual basis, strengths, and limitations of these methods are discussed. To our knowledge, MADDERS is the only system available to comprehensively evaluate inappropriate medication use events prospectively to determine the underlying intent. MADDERS can also be applied retrospectively to completed trial data. SR-MAD can be used prospectively; additional development may be required to standardize its implementation and fully appraise the intent of inappropriate use events. Additional research is needed to further demonstrate the validity and utility of MADDERS as well as SR-MAD., Perspective: Identifying a medication's abuse potential requires assessing inappropriate medication use events in clinical trials on the basis of a standardized event classification system. The strengths and limitations of the 2 published methods designed to evaluate inappropriate medication use events are reviewed, with recommended considerations for further development and current implementation., (Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials., Perspective: The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability., (Copyright © 2017 American Pain Society. All rights reserved.)

Unlabelled: The recently proposed Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION)-American Pain Society (APS) Pain Taxonomy (AAPT) provides an evidence-based, multidimensional, chronic pain classification system. Psychosocial factors play a crucial role within several dimensions of the taxonomy. In this article, we discuss the evaluation of psychosocial factors that influence the diagnosis and trajectory of chronic pain disorders. We review studies in individuals with a variety of persistent pain conditions, and describe evidence that psychosocial variables play key roles in conferring risk for the development of pain, in shaping long-term pain-related adjustment, and in modulating pain treatment outcomes. We consider "general" psychosocial variables such as negative affect, childhood trauma, and social support, as well as "pain-specific" psychosocial variables that include pain-related catastrophizing, self-efficacy for managing pain, and pain-related coping. Collectively, the complexity and profound variability in chronic pain highlights the need to better understand the multidimensional array of interacting forces that determine the trajectory of chronic pain conditions., Perspective: The AAPT is an evidence-based chronic pain classification system in which psychosocial concepts and processes are essential in understanding the development of chronic pain and its effects. In this article we review psychosocial processes that influence the onset, exacerbation, and maintenance of chronic pain disorders., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress., Perspective: This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Measurement of inappropriate medication use events (eg, abuse or misuse) in clinical trials is important in characterizing a medication's abuse potential. However, no gold standard assessment of inappropriate use events in clinical trials has been identified. In this systematic review, we examine the measurement properties (ie, content validity, cross-sectional reliability and construct validity, longitudinal construct validity, ability to detect change, and responder definitions) of instruments assessing inappropriate use of opioid and nonopioid prescription medications to identify any that meet U.S. and European regulatory agencies' rigorous standards for outcome measures in clinical trials. Sixteen published instruments were identified, most of which were not designed for the selected concept of interest and context of use. For this reason, many instruments were found to lack adequate content validity (or documentation of content validity) to evaluate current inappropriate medication use events; for example, evaluating inappropriate use across the life span rather than current use, including items that did not directly assess inappropriate use (eg, questions about anger), or failing to capture information pertinent to inappropriate use events (eg, intention and route of administration). In addition, the psychometric data across all instruments were generally limited in scope. A further limitation is the heterogeneous, nonstandardized use of inappropriate medication use terminology. These observations suggest that available instruments are not well suited for assessing current inappropriate medication use within the specific context of clinical trials. Further effort is needed to develop reliable and valid instruments to measure current inappropriate medication use events in clinical trials., Perspective: This systematic review evaluates the measurement properties of inappropriate medication use (eg, abuse or misuse) instruments to determine whether any meet regulatory standards for clinical trial outcome measures to assess abuse potential., (Copyright © 2015 American Pain Society. All rights reserved.)

Unlabelled: Current approaches to classification of chronic pain conditions suffer from the absence of a systematically implemented and evidence-based taxonomy. Moreover, existing diagnostic approaches typically fail to incorporate available knowledge regarding the biopsychosocial mechanisms contributing to pain conditions. To address these gaps, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration and the American Pain Society (APS) have joined together to develop an evidence-based chronic pain classification system called the ACTTION-APS Pain Taxonomy. This paper describes the outcome of an ACTTION-APS consensus meeting, at which experts agreed on a structure for this new taxonomy of chronic pain conditions. Several major issues around which discussion revolved are presented and summarized, and the structure of the taxonomy is presented. ACTTION-APS Pain Taxonomy will include the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. In coming months, expert working groups will apply this taxonomy to clusters of chronic pain conditions, thereby developing a set of diagnostic criteria that have been consistently and systematically implemented across nearly all common chronic pain conditions. It is anticipated that the availability of this evidence-based and mechanistic approach to pain classification will be of substantial benefit to chronic pain research and treatment., Perspective: The ACTTION-APS Pain Taxonomy is an evidence-based chronic pain classification system designed to classify chronic pain along the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Over the past decade, considerable research has accumulated showing that chronic pain patients experiencing high levels of negative affect (NA) are at increased risk for prescription opioid misuse. The primary objective of the present study was to examine the factors that underlie the association between NA and prescription opioid misuse among patients with chronic pain. In this study, 82 patients with chronic musculoskeletal pain being prescribed opioid medication completed the Current Opioid Misuse Measure, a well-validated self-report questionnaire designed to assess prescription opioid misuse. Patients were also asked to complete self-report measures of pain intensity, NA, and opioid craving. A bootstrapped multiple mediation analysis was used to examine the mediating role of patients' pain intensity and opioid craving in the association between NA and prescription opioid misuse. Consistent with previous research, we found a significant association between NA and prescription opioid misuse. Interestingly, results revealed that opioid craving, but not pain intensity, mediated the association between NA and opioid misuse. The Discussion addresses the potential psychological and neurobiological factors that might contribute to the interrelationships among NA, opioid craving, and prescription opioid misuse in patients with pain. The clinical implications of our findings are also discussed., Perspective: Our study provides new insights into the factors that underlie the association between negative affect and prescription opioid misuse in patients with chronic pain. Our findings could have important clinical implications, particularly for patients being prescribed opioid medication, and for reducing rates of opioid misuse in patients with pain., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Little is known about whether patients with chronic pain treated with opioids experience craving for their medications, whether contextual cues may influence craving, or if there is a relationship between craving and medication compliance. We hypothesized that craving for prescription opioids would be significantly correlated with the urge for more medication, preoccupation with the next dose, and current mood symptoms. We studied craving in 62 patients with chronic pain who were at low or high risk for opioid misuse, while they were enrolled in an RCT to improve prescription opioid medication compliance. Using electronic diaries, patients completed ratings of craving at monthly clinic visits and daily during a 14-day take-home period. Both groups consistently endorsed craving, whose levels were highly correlated (P < .001) with urge, preoccupation, and mood. The intervention to improve opioid compliance in the high-risk group was significantly associated with a rate of decrease in craving over time in comparison to a high-risk control group (P < .05). These findings indicate that craving is a potentially important psychological construct in pain patients prescribed opioids, regardless of their level of risk to misuse opioids. Targeting craving may be an important intervention to decrease misuse and improve prescription opioid compliance., Perspective: Patients with noncancer pain can crave their prescription opioids, regardless of their risk for opioid misuse. We found craving to be highly correlated with the urge to take more medication, fluctuations in mood, and preoccupation with the next dose, and to diminish with a behavioral intervention to improve opioid compliance., (Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: This study employed quantitative sensory testing (QST) to evaluate pain responses in chronic spinal pain patients at low risk and high risk for opioid misuse, with risk classification based on scores on the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R). Patients were further subgrouped according to current use of prescription opioids. Of the 276 chronic pain patients tested, approximately 65% were taking opioids; a median split was used to further categorize these patients as being on lower or higher doses of opioids. The high-risk group (n = 161) reported higher levels of clinical pain, had lower pressure and thermal pain thresholds at multiple body sites, had lower heat pain tolerance, and rated repetitive mechanical stimuli as more painful relative to the low-risk group (n = 115; P's < .01). In contrast, QST measures did not differ across opioid groups. Multiple linear regression analysis suggested that indices of pain-related distress (ie, anxiety and catastrophizing about pain) were also predictive of hyperalgesia, particularly in patients taking opioids. Collectively, regardless of opioid status, the high-risk group was hyperalgesic relative to the low-risk group; future opioid treatment studies may benefit from the classification of opioid risk, and the examination of pain sensitivity and other factors that differentiate high- and low-risk groups., Perspective: This study demonstrates that chronic spinal pain patients at high risk for misuse of prescription opioids are more pain-sensitive than low-risk patients, whether or not they are currently taking opioids. Indices of pain-related distress were important predictors of pain sensitivity, particularly among those patients taking opioids for pain., (Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Comorbid psychopathology is a variable not explored in the acupuncture RCTs that could explain whether subgroups of patients with chronic low back pain have differential responses to acupuncture or placebo treatments. This was a controlled, blinded, crossover trial of verum acupuncture and validated sham acupuncture in 40 CLBP patients, with a Low or High level of psychiatric comorbidity. They completed a 0 to 10 rating scale for pain at the beginning and end of each treatment session, and rated their expectations for change in pain. Verum acupuncture was performed at Large Intestine 4 on the dorsal right hand for 30 minutes by a licensed acupuncturist. Data analysis used percent improvement in pain as the primary outcome for each of the treatment sessions. Both groups (21 Low and 19 High) reported significant analgesia with verum acupuncture needling, mean 33%, P = .9 for difference between groups; and with placebo, 26%, P = .09. In both groups, expectations were only a significant predictor of verum acupuncture response, P = .002, such that those with greater expectations had greater pain relief. Psychiatric comorbidity does not significantly impact acupuncture or placebo acupuncture analgesia in CLBP. It does not affect the positive impact of expectations on reported pain relief from real acupuncture., Perspective: Psychiatric comorbidity may predict differences between acupuncture and placebo responses, not otherwise seen in the RCTs for low back pain. Using a blinded, crossover design, we report that it does not predict outcome, nor does it seem to modify the effect of expectancy (a known predictor) on acupuncture response., (Copyright (c) 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: This is a longitudinal predictive study to examine gender differences in the clinical correlates of risk for opioid misuse among chronic pain patients prescribed opioids for pain. Two hundred seventy-five male and 335 female patients prescribed opioids for chronic noncancer pain were asked to complete a series of baseline questionnaires, including the revised Screener and Opioid Assessment for Pain Patients (SOAPP-R). After 5 months, the subjects were administered a structured prescription drug use interview (Prescription Drug Use Questionnaire; PDUQ) and submitted a urine sample for toxicology assessment. Their treating physicians also completed a substance misuse behavior checklist (Prescription Opioid Therapy Questionnaire; POTQ). At 5-month follow-up, women showed higher scores on the PDUQ (P < .05), whereas men had a higher incidence of physician-rated aberrant drug behavior on the POTQ (P < .05). An item analysis of the SOAPP-R, PDUQ, and POTQ showed that women tended to score higher on items relating to psychological distress, whereas the male patients tended to report having more legal and behavioral problems. These results suggest that risk factors associated with prescription opioid misuse may differ between men and women., Perspective: Understanding gender differences in substance abuse risk among chronic pain patients is important for clinical assessment and treatment. This study suggests that women are at greater risk to misuse opioids because of emotional issues and affective distress, whereas men tend to misuse opioids because of legal and problematic behavioral issues., (Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: We assessed the efficacy of dronabinol (Marinol capsules; Solvay Pharmaceuticals, Brussels, Belgium), a synthetic Delta(9)-THC (tetrahydrocannabinol), in 30 patients taking opioids for chronic pain to determine its potential analgesic effects as an adjuvant treatment. Phase I of this 2-phase study was a randomized, single-dose, double-blinded, placebo-controlled, crossover trial in which subjects were randomly administered either 10 mg or 20 mg of dronabinol or identical placebo capsules over the course of three, 8-hour visits. Baseline self-report measures, hourly ratings of pain intensity, pain relief, pain bothersomeness, treatment satisfaction, mood, side effects, and blood serum levels were obtained. Phase II was an extended open-label titrated trial of dronabinol as add-on medication to patients on stable doses of opioids. Results of the Phase I study showed that patients who received dronabinol experienced decreased pain intensity and increased satisfaction compared with placebo. No differences in benefit were found between the 20 mg and 10 mg doses. In the Phase II trial, titrated dronabinol contributed to significant relief of pain, reduced pain bothersomeness, and increased satisfaction compared with baseline. The incidence of side effects was dose-related. Overall, the use of dronabinol was found to result in additional analgesia among patients taking opioids for chronic noncancer pain., Perspective: This study examines the effect of adding a cannabinoid to the regimen of patients with chronic pain who report significant pain despite taking stable doses of opioids. The results of our preliminary study suggest that dronabinol, a synthetic THC, may have an additive effect on pain relief.

Unlabelled: The antidepressant amitriptyline is used as an adjuvant in the treatment of chronic pain. Among its many actions, amitriptyline blocks Na+ channels and nerves in several animal and human models. As perioperative intravenous lidocaine has been suggested to decrease postoperative pain, amitriptyline, because of its longer half-life time, might be more useful than lidocaine. However, the use of intravenous amitriptyline is not approved by the US Food and Drug Administration. We therefore investigated the adverse effects of preoperative intravenous amitriptyline in a typical phase 1A trial. After obtaining written Food and Drug Administration and institutional review board approval, we obtained written consent for preoperative infusion of amitriptyline in an open-label, dose-escalating design (25, 50, and 100 mg, n=5 per group). Plasma levels of amitriptyline/nortriptyline were determined, and adverse effects were recorded in a predetermined symptom list. Infusion of 25 and 50 mg amitriptyline appears to be well tolerated; however, the study was terminated when 1 subject in the 100-mg group developed severe bradycardia. Intravenous infusion of amitriptyline (25 to 50 mg over 1 hour) did not create side effects beyond dry mouth and drowsiness, or dizziness, in 2 of our 10 otherwise healthy participants receiving the 25- to 50-mg dose. An appropriately powered future trial is necessary to determine a potential role of amitriptyline in decreasing postoperative pain., Perspective: Amitriptyline potently blocks the persistently open Na+ channels, which are known to be instrumental in various pain states. As this occurs at very low plasma concentrations, a single preoperative intravenous infusion of amitriptyline could provide long-lasting pain relief and decrease the incidence of chronic pain.