An Interventional Response Phenotyping Study in Chronic Low Back Pain: Protocol for a Mechanistic Randomized Controlled Trial.

Evidence-based treatments for chronic low back pain (cLBP) typically work well in only a fraction of patients, and at present there is little guidance regarding what treatment should be used in which patients. Our central hypothesis is that an interventional response phenotyping study can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based treatments for cLBP. Thus, we will conduct a randomized controlled Sequential, Multiple Assessment, Randomized Trial (SMART) design study in cLBP with the following three aims. Aim 1: Perform an interventional response phenotyping study in a cohort of cLBP patients (n = 400), who will receive a sequence of interventions known to be effective in cLBP. For 4 weeks, all cLBP participants will receive a web-based pain self-management program as part of a run-in period, then individuals who report no or minimal improvement will be randomized to: a) mindfulness-based stress reduction, b) physical therapy and exercise, c) acupressure self-management, and d) duloxetine. After 8 weeks, individuals who remain symptomatic will be re-randomized to a different treatment for an additional 8 weeks. Using those data, we will identify the subsets of participants that respond to each treatment. In Aim 2, we will show that currently available, clinically derived measures, can predict differential responsiveness to the treatments. In Aim 3, a subset of participants will receive deeper phenotyping (n = 160), to identify new experimental measures that predict differential responsiveness to the treatments, as well as to infer mechanisms of action. Deep phenotyping will include functional neuroimaging, quantitative sensory testing, measures of inflammation, and measures of autonomic tone.

Discrepancies Between Perceived Benefit of Opioids and Self-Reported Patient Outcomes.

Objective: There is little empirical evidence supporting the long-term use of opioid therapy for chronic pain, suggesting the need to reevaluate the role of opioids in chronic pain management. Few studies have considered opioid use and opioid cessation from the perspective of the patient. Methods: This prospective structured interview study included 150 new patients seeking treatment for chronic pain at an outpatient tertiary care pain clinic. Results: Of the 150 patients, 56% (N = 84) reported current opioid use. Opioids users reported higher pain severity (t(137) = -3.75, P < 0.001), worse physical functioning (t(136) = -3.82, P < 0.001), and more symptoms of depression (t(136) = -1.98, P = 0.050) than nonusers. Among opioid users, 45.6% reported high pain (>7), 60.8% reported low functioning (>7), and 71.4% reported less than a 30% reduction in pain severity since starting opioids, suggesting that many patients are unlikely to be receiving adequate benefit. Overall, 66.3% of current opioid users reported moderate to high opioid-related difficulties on the prescribed opioids difficulties scale, and patients with depression were more likely to report greater difficulties. There was no association between helpfulness of opioids over the past month and opioid-related difficulties (r(75) = -0.07, P = 0.559), current pain severity (r(72)=0.05, P = 0.705), or current pain interference (r(72) = 0.20, P = 0.095). Conclusions: Despite clinical indicators that question the benefit, patients may continue to report that their opioids are helpful. Such discrepancies in patients' perceptions will likely pose significant barriers for implementing opioid cessation guidelines in clinical practice.

Pressure sensitivity and phenotypic changes in patients with suspected opioid-induced hyperalgesia being withdrawn from full mu agonists.

OBJECTIVES: To assess changes in phenotype and pressure sensitivity in patients with suspected opioid-induced-hyperalgesia (OIH) after transitioning to buprenorphine. METHODS: Twenty patients with suspected OIH were enrolled to transition to buprenorphine therapy. Patients completed validated self-report measures at baseline and at 1, 4, 8 weeks, and 6 months after initiation of buprenorphine along with quantitative sensory testing including measures of pressure pain threshold, pain tolerance and Pain 50 (a pain intensity rating). RESULTS: 20 patients were enrolled, 17 were treated with buprenorphine and 11 completed all assessment points. We found that after transitioning to buprenorphine, patients on higher opioid doses (≥100mg oral morphine equivalents) had significant improvements for some measures including decreased pain severity and fibromyalgia survey scores, fewer neuropathic pain features, less catastrophizing, fewer depressive symptoms, and improved functioning 1-week after transitioning to buprenorphine with an eventual return back to baseline. Although not statistically significant, patients on high dose opioids (≥100mg OME) also showed a trend of decreased pressure sensitivity 1-week after transitioning to buprenorphine with a gradual return back to baseline. CONCLUSIONS: Our study is the first to look at pressure pain sensitivity in patients who were taking opioids and transitioned to buprenorphine. These results suggest that the patients most likely to benefit from buprenorphine therapy are those on higher doses. In addition, the eventual return back to baseline on measures of pain phenotype and pressure sensitivity suggests that buprenorphine may over time result in a return of the hyperalgesic effects of a full mu agonist.

Pressure Pain Sensitivity in Patients With Suspected Opioid-Induced Hyperalgesia.

BACKGROUND AND OBJECTIVES: This study was designed to test whether a brief quantitative sensory testing assessment could be used to detect hyperalgesia in patients with suspected opioid-induced hyperalgesia (OIH). METHODS: Twenty patients on long-term opioid therapy with suspected OIH were recruited along with 20 healthy controls. Pressure pain threshold, Pain50, a measure of intermediate suprathreshold pressure pain sensitivity, and tolerance levels were evaluated. As a secondary outcome, changes in pressure pain sensitivity after intravenous administration of placebo (saline) and fentanyl (1.5 µg/kg) were assessed. RESULTS: There were no significant differences in pain measures between healthy controls and patients. However, there was an association between higher doses of opioids and having a lower pain tolerance (r = -0.46, P = 0.041) and lower Pain50 (r = -0.46, P = 0.044), which was consistent with the hypothesis. Patients on more than 100 mg oral morphine equivalents displayed decreased pressure pain tolerance compared with patients taking less than 100 mg oral morphine equivalents (P = 0.042). In addition, male patients showed a hyperalgesic response to fentanyl administration, which was significant for the Pain50 measure (P = 0.002). CONCLUSIONS: Whereas there were no differences between patients suspected of having OIH and the healthy controls, the finding that higher doses of opioids were associated with more sensitivity suggests that dose might be an important factor in the development of hyperalgesia. In addition, male patients demonstrated a hyperalgesic response after a bolus of fentanyl. Future studies are needed to develop better diagnostics for detecting hyperalgesia in the clinical setting.

Characteristics of chronic pain patients who take opioids and persistently report high pain intensity.

BACKGROUND AND OBJECTIVES: The use of self-report questionnaires to detect characteristics of altered central pain processing, as seen in centralized pain disorders such as fibromyalgia, allow for the epidemiological studies of pain patients. Here, we assessed the relationship between reporting high levels of pain while taking opioids and the presence of characteristics associated with centralized pain. METHODS: We evaluated 582 patients taking opioid medications using validated measures of clinical pain, neuropathic pain symptoms, mood, and functioning. A multivariate linear regression model was used to assess the association between levels of pain while taking opioids and presenting with characteristics consistent with having centralized pain. RESULTS: We found that 49% of patients taking opioids continued to report severe pain (≥ 7/10). In multivariate analysis, factors associated with having higher levels of pain in opioid users included higher fibromyalgia survey scores (P = 0.001), more neuropathic pain symptoms (P < 0.001), and higher levels of depression (P = 0.002). Although only 3.2% were given a primary diagnosis of fibromyalgia by their physician, 40.8% met American College of Rheumatology survey criteria for fibromyalgia. CONCLUSIONS: Our findings suggest that patients with persistently high pain scores despite opioid therapy are more likely than those with lower levels of pain to present with characteristics associated with having centralized pain. This study cannot determine whether these characteristics were present before (fibromyalgia-like patient) or after the initiation of opioids (opioid-induced hyperalgesia). Regardless, patients with a centralized pain phenotype are thought to be less responsive to opioids and may merit alternative approaches.

Prevalence of the fibromyalgia phenotype in patients with spine pain presenting to a tertiary care pain clinic and the potential treatment implications.

OBJECTIVE: Injections for spinal pain have high failure rates, emphasizing the importance of patient selection. It is possible that detecting the presence of a fibromyalgia (FM)-like phenotype could aid in prediction, because in these individuals a peripheral injection would not address pain due to alterations in central neurotransmission. We undertook this study to test the hypothesis that patients who have spine pain meeting survey criteria for FM would be phenotypically distinct from those who do not. METHODS: We studied 548 patients diagnosed as having primary spine pain. All patients completed validated self-report questionnaires, including the Brief Pain Inventory, the PainDETECT questionnaire, the Hospital Anxiety and Depression Scale, measures of physical function, and the FM criteria and severity scales. RESULTS: Forty-two percent of the patients were FM positive according to the FM criteria and severity scales. Compared with FM-negative patients, FM-positive patients were more likely to be younger, unemployed, and receiving compensation for pain and to have greater pain severity and pain interference and more neuropathic pain descriptors as well as higher levels of depression and anxiety and a lower level of physical function (P < 0.002 for each comparison). Female sex, neuropathic pain, pain interference, and anxiety were independently predictive of FM status in a multivariate analysis (P < 0.01 for all variables). Receiver operating characteristic curve analysis showed a strength of association of 0.80 as measured by the cross-validated C statistic. CONCLUSION: Using the FM criteria and severity scales, we demonstrated profound phenotypic differences in a population of patients with spine pain. Although centralized pain cannot be confirmed with a self-report instrument alone, the pathophysiology of FM may help explain a portion of the variability of responses to spine interventions.

Interventional techniques in the management of chronic spinal pain: evidence-based practice guidelines.

BACKGROUND: The lifetime prevalence of spinal pain has been reported as 54% to 80%, with as many as 60% of patients continuing to have chronic pain five years or longer after the initial episode. Spinal pain is associated with significant economic, societal, and health impact. Available evidence documents a wide degree of variance in the definition and the practice of interventional pain management. OBJECTIVE: To develop evidence-based clinical practice guidelines for interventional techniques in the management of chronic spinal pain, with utilization of all types of evidence, applying an evidence-based approach, with broad representation of specialists from academic and clinical practices. DESIGN: A systematic review of diagnostic and therapeutic interventions applied in managing chronic spinal pain by a policy committee. Design consisted of formulation of essentials of guidelines and a series of potential evidence linkages representing conclusions, and statements about relationships between clinical interventions and outcomes. METHODS: The elements of the guideline preparation process included literature searches, literature synthesis, systematic review, consensus evaluation, open forum presentation, formal endorsement by the Board of Directors of the American Society of Interventional Pain Physicians (ASIPP), and blinded peer review. Methodologic quality evaluation criteria utilized included AHRQ criteria, QUADAS criteria, and Cochrane review criteria. The designation of levels of evidence was from Level I (conclusive), Level II (strong), Level III (moderate), Level IV (limited), to Level V (indeterminate). RESULTS: The accuracy of facet joint nerve blocks was strong in the diagnosis of lumbar and cervical facet joint pain, whereas, it was moderate in the diagnosis of thoracic facet joint pain. The evidence was strong for lumbar discography, whereas, the evidence was limited for cervical and thoracic discography. The evidence was moderate for transforaminal epidural injections or selective nerve root blocks in the preoperative evaluation of patients with negative or inconclusive imaging studies. The evidence was moderate for sacroiliac joint injections in the diagnosis of sacroiliac joint pain. The evidence for therapeutic lumbar intraarticular facet injections of local anesthetics and steroids was moderate for short-term improvement and limited for long-term improvement, whereas, it was negative for cervical facet joint injections. The evidence for lumbar and cervical medial branch blocks was moderate. The evidence for medial branch neurotomy was moderate to strong for relief of chronic low back and neck pain. The evidence for caudal epidural steroid injections was strong for short-term relief and moderate for long-term relief in managing chronic low back and radicular pain, and limited in managing pain of postlumbar laminectomy syndrome. The evidence for interlaminar epidural steroid injections was strong for short-term relief and limited for long-term relief in managing lumbar radiculopathy, whereas, for cervical radiculopathy the evidence was moderate. The evidence for transforaminal epidural steroid injections was strong for short-term and moderate for long-term improvement in managing lumbar nerve root pain, whereas, it was moderate for cervical nerve root pain and limited for lumbar post laminectomy syndrome and spinal stenosis. The evidence for percutaneous epidural adhesiolysis was strong. For spinal endoscopic adhesiolysis, the evidence was strong for short-term relief and moderate for long-term relief. For sacroiliac intraarticular injections, the evidence was moderate for short-term relief and limited for long-term relief. The evidence for radiofrequency neurotomy for sacroiliac joint pain was indeterminate. The evidence for intradiscal electrothermal therapy was strong for short-term relief and moderate for long-term relief in managing chronic discogenic low back pain, whereas, for nucleoplasty, the evidence was limited. The evidence for spinal cord stimulation in failed back surgery syndrome and complex regional pain syndrome was strong for short-term relief and moderate for long-term relief. The evidence for implantable intrathecal infusion systems was moderate to strong. CONCLUSION: These guidelines included the evaluation of evidence for diagnostic and therapeutic procedures in managing chronic spinal pain and recommendations for managing spinal pain. However, these guidelines do not constitute inflexible treatment recommendations. These guidelines do not represent "a standard of care".