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Journal: Pain


This randomized controlled trial was performed to investigate whether placebo effects in chronic low back pain could be harnessed ethically by adding open-label placebo (OLP) treatment to treatment as usual (TAU) for 3 weeks. Pain severity was assessed on three 0- to 10-point Numeric Rating Scales, scoring maximum pain, minimum pain, and usual pain, and a composite, primary outcome, total pain score. Our other primary outcome was back-related dysfunction, assessed on the Roland-Morris Disability Questionnaire. In an exploratory follow-up, participants on TAU received placebo pills for 3 additional weeks. We randomized 97 adults reporting persistent low back pain for more than 3 months' duration and diagnosed by a board-certified pain specialist. Eighty-three adults completed the trial. Compared to TAU, OLP elicited greater pain reduction on each of the three 0- to 10-point Numeric Rating Scales and on the 0- to 10-point composite pain scale (P < 0.001), with moderate to large effect sizes. Pain reduction on the composite Numeric Rating Scales was 1.5 (95% confidence interval: 1.0-2.0) in the OLP group and 0.2 (-0.3 to 0.8) in the TAU group. Open-label placebo treatment also reduced disability compared to TAU (P < 0.001), with a large effect size. Improvement in disability scores was 2.9 (1.7-4.0) in the OLP group and 0.0 (-1.1 to 1.2) in the TAU group. After being switched to OLP, the TAU group showed significant reductions in both pain (1.5, 0.8-2.3) and disability (3.4, 2.2-4.5). Our findings suggest that OLP pills presented in a positive context may be helpful in chronic low back pain.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Concepts: Low back pain, Randomized controlled trial, Statistical significance, Pharmaceutical industry, Clinical research, Placebo, Acupuncture, Effect size


Animal and human studies indicate that electrical stimulation of DRG neurons may modulate neuropathic pain signals.ACCURATE, a pivotal, prospective, multi-center, randomized-comparative effectiveness trial, was conducted in 152 subjects diagnosed with complex regional pain syndrome (CRPS) or causalgia in the lower extremities. Subjects received neurostimulation of the DRG or dorsal column (SCS). The primary endpoint was a composite of safety and efficacy at 3 months and subjects were assessed through 12 months for long term outcomes and adverse events. The pre-defined primary composite endpoint of treatment success was met for subjects with a permanent implant who reported 50% or greater decrease in VAS from pre-implant baseline and who did not report any stimulation-related neurological deficits.No subjects reported stimulation-related neurological deficits. The percentage of subjects receiving ≥ 50% pain relief and treatment success was greater in the DRG arm (81.2%) versus the SCS arm (55.7%, p<0.001) at 3 months. Device-related and serious adverse events were not different between the 2 groups. DRG stimulation also demonstrated greater improvements in quality of life and psychological disposition. Finally, subjects using DRG stimulation reported less postural variation in paresthesia (p<0.001) and reduced extraneous stimulation in non-painful areas (p=0.014), indicating DRG stimulation provided more targeted therapy to painful parts of the lower extremities.As the largest prospective, randomized comparative effectiveness trial to date, the results show DRG stimulation provided a higher rate of treatment success with less postural variation in paresthesia intensity compared to SCS.

Concepts: Nervous system, Dorsal root ganglion, Neurology, Pain, Nociception, Suffering, Complex regional pain syndrome, Peripheral neuropathy


A fundamental question for placebo research is whether such responses are a predisposition, quantifiable by brain characteristics. We examine this issue in chronic back pain (CBP) patients who participated in a double-blind brain imaging (functional magnetic resonance imaging) clinical trial. We recently reported that when the 30 CBP participants were treated, for 2weeks, with topical analgesic or no drug patches, pain and brain activity decreased independently of treatment type and thus were attributed to placebo responses. Here we examine in the same group brain markers for predicting placebo responses-that is, for differentiating between posttreatment persistent CBP (CBPp) and decreasing CBP (CBPd) groups. At baseline, pain and brain activity for rating spontaneous fluctuations of back pain were not different between the 2 groups. However, on the basis of brain activity differences after treatment, we identified that at baseline the extent of information shared (functional connectivity) between left medial prefrontal cortex and bilateral insula accurately (0.8) predicted posttreatment groups. This was validated in an independent cohort. Additionally, by means of frequency domain contrasts, we observe that at baseline, left dorsolateral prefrontal cortex high-frequency oscillations also predicted treatment outcomes and identified an additional set of functional connections distinguishing treatment outcomes. Combining medial and lateral prefrontal functional connections, we observe a statistically higher accuracy (0.9) for predicting posttreatment groups. These findings indicate that placebo response can be identified a priori at least in CBP, and that neuronal population interactions between prefrontal cognitive and pain processing regions predetermine the probability of placebo response in the clinical setting.

Concepts: Clinical trial, Brain, Magnetic resonance imaging, Cerebrum, Pain, Placebo, Attention versus memory in prefrontal cortex, Premotor cortex


Minocycline strongly inhibits microglial activation, which contributes to central sensitization, a major mechanism underlying chronic pain development. We hypothesized that the perioperative administration of minocycline might decrease persistent pain after lumbar discectomy. We randomly assigned 100 patients undergoing scheduled lumbar discectomy to placebo and minocycline groups. The minocycline group received 100mg minocycline orally, twice daily, beginning the evening before surgery and continuing for 8days. The primary outcome was the change in lower limb pain intensity at rest between baseline and 3months. Secondary outcomes were pain intensity on movement, the incidence of persistent pain and chronic neuropathic pain, back pain intensity at rest and on movement, and changes in Neuropathic Pain Symptom Inventory, Brief Pain Inventory, and Roland-Morris scores at 3months. An intention-to-treat analysis was performed for patients assessed from the day before surgery to 3months. The decrease in lower limb pain intensity was similar in the placebo and minocycline groups, both at rest -1.7±1.6 vs -2.3±2.4 and on movement -2.5±2.1 vs -3.4±2.9. The incidence and intensity of neuropathic pain and functional scores did not differ between the minocycline and placebo groups. Exploratory analysis suggested that minocycline might be effective in a subgroup of patients with predominantly deep spontaneous pain at baseline. Perioperative minocycline administration for 8days does not improve persistent pain after lumbar discectomy.

Concepts: Game theory, Randomized controlled trial, Rheumatoid arthritis, Pain, Randomness, Microglia, Chronic pain, Neuropathic pain


There is evidence that inflammatory processes are involved at least in the early phase of complex regional pain syndrome (CRPS). We compared a panel of pro- and anti-inflammatory cytokines in skin blister fluids and serum from patients with CRPS and patients with upper limb pain of other origin (non-CRPS) in the early stage (< 1 year) and after six months of pain treatment.

Concepts: Complex regional pain syndrome


Testicular pain syndrome (TPS), defined as an intermittent or constant pain in one or both testicles for at least 3 months, resulting in significant reduction of daily activities, is common. Microsurgical denervation of the spermatic cord (MDSC) has been suggested as an effective treatment option. The study population comprised 180 TPS patients, admitted to our outpatient urology clinic between 1999 and 2011. On three different occasions, patients were offered a double-blind, placebo-controlled temporary blockade of the spermatic cord. A single blockade consisted of 10 mL 2% lidocaine, 10 mL 0.25% bupivacaine or 10 mL 0.9% sodium chloride. If the results of these blockades were positive, MDSC was offered. All MDSCs were performed by a single urologist (MTWTL) using an inguinal approach. Pain reduction was determined at prospective follow-up. 180 patients were evaluated. Most patients (61.1%) had undergone a scrotal or inguinal procedure. Patients had complaints during sexual activities (51.7%), sitting (37.5%) and/or cycling (36.7%). 189 randomized blockades were offered to all patients. There was a positive response in 37% and a negative response in 51%. MDSC was performed on 58 testicular units including 3 patients with a negative outcome of the blockades. At mean follow-up of 42.8 months, 86.2% had a ⩾50% reduction of pain and 51.7% were completely pain free. MDSC is a valuable treatment option for TPS patients as in this study 86.2% experienced a ⩾50% reduction of pain. To prevent superfluous diagnostics and treatment, it is mandatory to follow a systematic protocol in the treatment of TPS.

Concepts: Sodium chloride, Testicle, Sodium, Male reproductive system, Scrotum, Spermatic cord, Testicular torsion, Blockade


Implanted vagus nerve stimulation (VNS) has been used to treat seizures and depression. In this study, we explore the mechanism of action of non-invasive vagus nerve stimulation (nVNS) for the treatment of trigeminal allodynia. Rats were repeatedly infused with inflammatory mediators directly onto the dura, which leads to chronic trigeminal allodynia. nVNS for 2min decreases periorbital sensitivity in rats with periorbital trigeminal allodynia for up to 3.5hr after stimulation. Using microdialysis, we quantified levels of extracellular neurotransmitters in the trigeminal nucleus caudalis (TNC). Allodynic rats showed a 7.7±0.9 fold increase in extracellular glutamate in the TNC following i.p. administration of the chemical headache trigger, glyceryl trinitrate (GTN; 0.1mg/kg). Allodynic rats, which received nVNS, had only a 2.3±0.4 fold increase in extracellular glutamate following GTN similar to the response in control naive rats. When nVNS was delayed until 120min after GTN treatment, the high levels of glutamate in the TNC were reversed following nVNS. The nVNS stimulation parameters used in this study did not produce significant changes in blood pressure or heart rate. These data suggest that nVNS may be used to treat trigeminal allodynia.

Concepts: Inflammation, Nervous system, Vagus nerve, Cranial nerves, Acetylcholine, Carotid sinus, Vagus nerve stimulation, Vagus


A primary goal in managing pain is to reduce pain and increase physical function (PF). This goal is also tied to continuing payment for treatment services in many practice guidelines. Pain interference (PI) is often used as a proxy for measurement and reporting of PF in these guidelines. A common assumption is that reductions in PI will translate into improvement in PF over time. This assumption needs to be tested in a clinical environment. Consequently, we used the patient reported outcomes measurement information system (PROMIS) to describe the topology of the longitudinal relationship between PI in relation to PF.Longitudinal data of 389 people with chronic pain seeking healthcare demonstrated that PI partially explained the variance in PF at baseline (r = -0.50) and over 90 days of care(r = -0.65). The relationship between pain intensity and PF was not significant when PI was included as a mediator. A parallel process latent growth curve model analysis showed a weak, unidirectional relationship (β = 0.18) between average PF scores and changes in PI over the course of 90 days of care, and no relationship between average PI scores and changes in PF across time.Although PI and PF appear moderately related when measured concurrently, they do not cluster closely together across time. The differential pathways between these two domains suggest that therapies which target both the consequences of pain on relevant aspects of persons' lives, and capability to perform physical activities are likely required for restoration of a vital life.

Concepts: Measurement, Pain, Demonstration, Chronic pain


The redefinition of neuropathic pain as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system,” which was suggested by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the “definite” level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Concepts: Clinical trial, Pain, Sensory system, Creative Commons


The “Gate Control Theory of Pain” of 1965 became famous for integrating clinical observations and the understanding of spinal dorsal horn circuitry at that time into a testable model. While it became rapidly clear that spinal circuitry is much more complex than proposed by Melzack and Wall, their prediction of the clinical efficacy of transcutaneous electrical nerve stimulation (TENS) and spinal cord stimulation (SCS) has left an important clinical legacy also 50 years later. In the meantime it has been recognized that the sensitivity of the nociceptive system can be decreased or increased, and that this “gain control” can occur at peripheral, spinal and supraspinal levels. The resulting changes in pain sensitivity can be rapidly reversible or persistent, highly localized or widespread. Profiling of spatio-temporal characteristics of altered pain sensitivity (evoked pain to mechanical and/or heat stimuli) allows implications on the mechanisms likely active in a given patient, including peripheral or central sensitization, intraspinal or descending inhibition. This hypothesis generation in the diagnostic process is an essential step towards a mechanism-based treatment of pain. The challenge now is to generate the rational basis of multimodal pain therapy algorithms by including profile-based stratification of patients into studies on efficacy of pharmacological and non-pharmacological treatment modalities. This review outlines the current evidence base for this approach.

Concepts: Scientific method, Mathematics, Pain, Hypothesis, Control theory, Process control, PID controller, Control engineering