OBJECTIVE: To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue. METHODS: Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain. RESULTS: When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported. CONCLUSION: The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.
Bruehl S, Apkarian V, Ballantyne JC, et al. Personalized medicine and opioid analgesic prescribing for chronic pain: opportunities and challenges. J. Pain. 2013;14(2):103-113.
UNLABELLED: Use of opioid analgesics for pain management has increased dramatically over the past decade, with corresponding increases in negative sequelae including overdose and death. There is currently no well-validated objective means of accurately identifying patients likely to experience good analgesia with low side effects and abuse risk prior to initiating opioid therapy. This paper discusses the concept of data-based personalized prescribing of opioid analgesics as a means to achieve this goal. Strengths, weaknesses, and potential synergism of traditional randomized placebo-controlled trial (RCT) and practice-based evidence (PBE) methodologies as means to acquire the clinical data necessary to develop validated personalized analgesic-prescribing algorithms are overviewed. Several predictive factors that might be incorporated into such algorithms are briefly discussed, including genetic factors, differences in brain structure and function, differences in neurotransmitter pathways, and patient phenotypic variables such as negative affect, sex, and pain sensitivity. Currently available research is insufficient to inform development of quantitative analgesic-prescribing algorithms. However, responder subtype analyses made practical by the large numbers of chronic pain patients in proposed collaborative PBE pain registries, in conjunction with follow-up validation RCTs, may eventually permit development of clinically useful analgesic-prescribing algorithms. PERSPECTIVE: Current research is insufficient to base opioid analgesic prescribing on patient characteristics. Collaborative PBE studies in large, diverse pain patient samples in conjunction with follow-up RCTs may permit development of quantitative analgesic-prescribing algorithms that could optimize opioid analgesic effectiveness and mitigate risks of opioid-related abuse and mortality.
Carroll I, Hah J, Mackey S, et al. Perioperative interventions to reduce chronic postsurgical pain. J. Reconstr. Microsurg. 2013;29(4):213-222.
Approximately 10% of patients following a variety of surgeries develop chronic postsurgical pain. Reducing chronic postoperative pain is especially important to reconstructive surgeons because common operations such as breast and limb reconstruction have even higher risk for developing chronic postsurgical pain. Animal studies of posttraumatic nerve injury pain demonstrate that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviors-so called “preventative analgesia.” In animal models, perineural local anesthetic, systemic intravenous local anesthetic, perineural clonidine, systemic gabapentin, systemic tricyclic antidepressants, and minocycline have each been shown to reduce pain behaviors days to weeks after treatment. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain. Recent clinical trial data show that there is an opportunity during the perioperative period to dramatically reduce the incidence and severity of chronic postsurgical pain. The surgeon, working with the anesthesiologist, has the ability to modify both early and chronic postoperative pain by implementing an evidence-based preventative analgesia plan.
Dworkin RH, Connor ABO, Kent J, et al. Interventional management of neuropathic pain: NeuPSIG recommendations. Pain. 2013;154(11):2249-2261.
Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long-term studies, and head-to-head comparisons among different interventional and noninterventional treatments.
Kong J-T, Schnyer RN, Johnson KA, Mackey S. Understanding central mechanisms of acupuncture analgesia using dynamic quantitative sensory testing: a review. Evid. Based. Complement. Alternat. Med. 2013;2013:187182.
We discuss the emerging translational tools for the study of acupuncture analgesia with a focus on psychophysical methods. The gap between animal mechanistic studies and human clinical trials of acupuncture analgesia calls for effective translational tools that bridge neurophysiological data with meaningful clinical outcomes. Temporal summation (TS) and conditioned pain modulation (CPM) are two promising tools yet to be widely utilized. These psychophysical measures capture the state of the ascending facilitation and the descending inhibition of nociceptive transmission, respectively. We review the basic concepts and current methodologies underlying these measures in clinical pain research, and illustrate their application to research on acupuncture analgesia. Finally, we highlight the strengths and limitations of these research methods and make recommendations on future directions. The appropriate addition of TS and CPM to our current research armamentarium will facilitate our efforts to elucidate the central analgesic mechanisms of acupuncture in clinical populations.
Kong J-T, Johnson KA, Balise RR, Mackey S. Test-retest reliability of thermal temporal summation using an individualized protocol. J. Pain. 2013;14(1):79-88.
UNLABELLED: Temporal summation (TS) refers to the increased perception of pain with repetitive noxious stimuli. It is a behavioral correlate of wind-up, the spinal facilitation of recurring C-fiber stimulation. In order to utilize TS in clinical pain research, it is important to characterize TS in a wide range of individuals and to establish its test-retest reliability. Building on a fixed-parameter protocol, we developed an individually adjusted protocol to broadly capture thermally generated TS. We then examined the test-retest reliability of TS within-day (intertrial intervals ranging from 2 to 30 minutes) and between-days (intersession interval of 7 days). We generated TS-like effects in 19 of the 21 participants. Strong correlations were observed across all trials over both days (intraclass correlation [ICC] [A, 10] = .97, 95% confidence level [CL] = .94-.99) and across the initial trials between days (ICC [A, 1] = .83, 95% CL = .58-.93). Repeated measures mixed-effects modeling demonstrated no significant within-day variation and only a small (5 out of 100 points) between-day variation. Finally, a Bland-Altman analysis suggested that TS is reliable across the range of observed scores. Without intervention, thermally-generated TS is generally stable within day and between days. PERSPECTIVE: Our study introduces a new strategy to generate thermal TS in a high proportion of individuals. This study confirms the test-retest reliability of thermal TS, supporting its use as a consistent behavioral correlate of central nociceptive facilitation.


Mackey S, Carroll I, Emir B, Murphy K, Whalen E, Dumenci L. Sensory pain qualities in neuropathic pain. J. Pain. 2012;13(1):58-63.
UNLABELLED: The qualities of chronic neuropathic pain (NeP) may be informative about the different mechanisms of pain. We previously developed a 2-factor model of NeP that described an underlying structure among sensory descriptors on the Short-Form McGill Pain Questionnaire. The goal of this study was to confirm the correlated 2-factor model of NeP. Individual descriptive scores from the Short-Form McGill Pain Questionnaire were analyzed. Confirmatory factor analysis was used to test a correlated 2-factor model. Factor 1 (stabbing pain) was characterized by high loadings on stabbing, sharp, and shooting sensory items; factor 2 (heavy pain) was characterized by high loadings on heavy, gnawing, and aching items. Results of the confirmatory factor analysis strongly supported the correlated 2-factor model. PERSPECTIVE: This article validates a model that describes the qualities of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. These data suggest that specific pain qualities may be associated with pain mechanisms or may be useful for predicting treatment response.
BACKGROUND: A patient s response to treatment may be influenced by the expectations that the patient has before initiating treatment. In the context of clinical trials, the influence of participant expectancy may blur the distinction between real and sham treatments, reducing statistical power to detect specific treatment effects. There is therefore a need for a tool that prospectively predicts expectancy effects on treatment outcomes across a wide range of treatment modalities. PURPOSE: To help assess expectancy effects, we created the Stanford Expectations of Treatment Scale (SETS): an instrument for measuring positive and negative treatment expectancies. Internal reliability of the instrument was tested in Study 1. Criterion validity of the instrument (convergent, discriminant, and predictive) was assessed in Studies 2 and 3. METHODS: The instrument was developed using 200 participants in Study 1. Reliability and validity assessments were made with an additional 423 participants in Studies 2 and 3. RESULTS: The final six-item SETS contains two subscales: positive expectancy (α = 0.81-0.88) and negative expectancy (α = 0.81-0.86). The subscales predict a significant amount of outcome variance (between 12% and 18%) in patients receiving surgical and pain interventions. The SETS is simple to administer, score, and interpret. CONCLUSION: The SETS may be used in clinical trials to improve statistical sensitivity for detecting treatment differences or in clinical settings to identify patients with poor treatment expectancies.