Stem cells: Targeting pain of spinal-cord injury
Nature 537, 7622 (2016). doi:10.1038/537588d
Neurons derived from human embryonic stem cells can reduce pain and other effects of spinal-cord injury in mice.Persistent nerve pain and loss of bladder control often follow spinal-cord injury, and may be linked to reduced signalling by the inhibitory neurotransmitter GABA. Thomas Fandel and
Although specific psychological disorders in complex regional pain syndrome (CRPS) have not been identified, studies suggest that CRPS patients may have increased rates of traumatic life events. Because these events do not always lead to apparent psychological symptoms, we systematically screened CRPS patients for posttraumatic stress disorder (PTSD) to determine if PTSD could be a risk factor for CRPS.
Consecutive CRPS patients referred to two university hospital centres (University of Erlangen, UMC Mainz) between December 2011 and April 2013 were prospectively examined using a diagnostic PTSD instrument (Post-traumatic Stress Diagnostic Scale (PDS). We also tested maladaptive coping strategies (brief-COPE inventory) and the PDS severity score as predictors for CRPS. Patients with non-CRPS extremity pain and healthy individuals were used as control groups.
We collected data from 152 patients with CRPS, 55 control patients and 55 age- and sex-matched healthy individuals. Fifty-eight CRPS patients (38%), six non-CRPS pain patients (10%) and two healthy individuals (4%) met diagnostic criteria for PTSD. Initial PTSD symptom onset was prior to CRPS in 50 CRPS patients (86%) and during the course of CRPS in eight patients. Results of a logistic regression revealed that the PTSD severity score was associated with CRPS (p < 0.0001). Maladaptive coping strategies (p < 0.0001) were related to PTSD.
posttraumatic stress disorder (PTSD) is more frequent in patients with CRPS than it is in the general population.
Research has not yet provided support for specific psychological predictors for CRPS.
Serotonin–norepinephrine reuptake inhibitors inhibit the reuptake of serotonin and noradrenalin and are used in the treatment of neuropathic pain. Animal studies suggest that milnacipran co-administered with opioids may potentiate the analgesic effect of μ-opioid receptor agonists. This study hypothesized that co-administration of milnacipran and buprenorphine would have a synergistic effect in evoked pain models in healthy subjects.
This was a randomized double-blinded, placebo-controlled, four-way cross-over, multiple dose clinical trial to investigate the analgesic effects of buprenorphine (placebo, 0.5, 1 and 3 μg/kg) in combination with milnacipran (placebo, 25 and 50 mg) in healthy subjects.
11 healthy men were enrolled in the study. Buprenorphine alone showed a dose–response relationship indicative of anti-nociception in the pain tests. Following milnacipran administration, no changes were seen in the pharmacodynamic measurements for pain, psychomotor function, body stability or eye movements. For the electrical tests, cold pressor test and pressure pain test, buprenorphine alone was superior when compared with buprenorphine plus milnacipran. No differences in pharmacodynamic variables, besides an increase in pupil/iris ratio, were observed after repeated administration of milnacipran 50 mg. Single and multiple doses of 25 or 50 mg milnacipran did not further potentiate the anti-nociceptive effects of buprenorphine.
Buprenorphine showed dose-dependent effects consistent with its pharmacological profile. Milnacipran alone did not affect any of the pain variables. The combination of both buprenorphine and milnacipran did not potentiate or show a synergistic effect on the pain models used in this study.
Buprenorphine is known to be a potent opioid agonist. Animal studies suggest that milnacipran co-administered with opioids may potentiate the analgesic effect of μ-opioid receptor agonists. Here, we found that buprenorphine showed a dose-dependent analgesic effect, but that no potentiation or synergy on a battery of evoked pain tasks could be observed after co-administration of both milnacipran and buprenorphine.
Tissue pH is lowered in inflamed tissues, and the increased proton concentration activates acid-sensing ion channels (ASICs), contributing to pain and hyperalgesia. ASICs can be upregulated by nerve growth factor (NGF). The aim of this study was to investigate two new human experimental pain models combining NGF- and acid-induced pain in a randomized, controlled, double-blind study.
In experiment 1, volunteers (N = 16) received an injection of either NGF or isotonic saline in each infrapatellar fat pad (IFP). One day after 5 mL of phosphate-buffered acidic saline was infused into each IFP at a rate of 20 mL/h. In experiment 2, the tibialis anterior (TA) muscle of additional volunteers (N = 16) was examined, following the same procedure except that the volume and infusion rate of acid were different (10 mL, 30 mL/h). Continuous pain ratings were recorded during and after acid infusions. In addition, soreness scores on a Likert scale and pressure pain thresholds (PPTs) were assessed.
The PPT of the IFP was significantly decreased at the NGF injection site on day 1, but acid-provoked pain ratings and the change in PPT from pre- to postinfusion between the knees were similar. In the muscle pain model, local mechanical hyperalgesia developed 3 h after the NGF injection and a significant additional decrease in PPT was found after acid infusion compared to preinfusion.
NGF sensitization in the IFP was not facilitated by acid, whereas an acid-provoked enhancement of muscle hyperalgesia was found. NGF sensitization of adipose tissue responds differently to acid provocation compared to muscle tissue.
Quantification of two novel pain models combining NGF and acid. Hyperalgesia developed after NGF injection in the infrapatellar fat pad, but it was not facilitated by acid provocation. Contrary, NGF-induced hyperalgesia in muscle tissue was enhanced by acid.
Patients with fibromyalgia (FM) exhibit significant clinical heterogeneity, in terms of physical, social and psychological functions, as well as therapeutic responses. Here, we examined FM patients in terms of pain, physical, social and psychological variables to identify clinical subgroups that may be predictive of treatment patterns.
A total of 313 FM patients were interviewed using a structured questionnaire that included sociodemographic data, current or past FM symptoms and current use of relevant medications. A K-means cluster analysis was conducted using variables reflecting tender points, the Fibromyalgia Impact Questionnaire, Beck Depression Inventory, State-Trait Anxiety Inventor and Social Support Scale.
Four distinct clusters were identified in these patients. Group 1 was characterized by high pain levels, severe physical and mental impairment and low social support. Group 2 had moderate pain and physical impairment, mild mental impairment and moderate social support. Group 3 had moderate pain, low physical and moderate mental impairment and low social support. Group 4 had low pain levels, nearly normal physical and mental function and high social support. Group 1 was more often a current or past smoker, more likely to have a variety of symptoms, including swelling, cognitive dysfunction, dizziness, syncope, oesophageal dysmotility, dyspepsia, irritable bladder, vulvodynia and restless leg syndrome.
We identified four subgroups of FM patients based on pain, physical, social and psychological function. These subgroups had different clinical symptoms and medication profiles, suggesting that FM may be better managed using a more comprehensive assessment of an individual patient's symptoms.
FM patients can be clustered into four distinct subgroups based on clinically measurable variables – pain, physical involvement, psychological function and social support. These subgroups had different clinical symptoms and medication profiles.
No core set of measurement tools exists to collect data within clinical practice. Such data could be useful as reference data to guide treatment decisions and to compare patient characteristics or treatment results within specific treatment settings.
The Dutch Dataset Pain Rehabilitation was developed which included the six domains of the IMMPACT core set and three new domains relevant in the field of rehabilitation (medical consumption, patient-specific goals and activities/participation). Between 2010 and 2013 the core set was implemented in 32 rehabilitation facilities throughout the Netherlands.
A total of 8200 adult patients with chronic pain completed the core set at first consultation with the rehabilitation physician. Adult patients (18–90 years) suffering from a long history of pain (38% >5 years) were referred. Patients had high medical consumption and less than half were working. Although patients were referred with diagnosis of low back pain or neck or shoulder pain, a large group (85%) had multisite pain (39% 2–5 painful body regions; 46% >5 painful body regions). Scores on psychosocial questionnaires were high, indicating high case complexity of referred patients. Reference data for subgroups based on gender, pain severity, pain locations and on pain duration are presented.
The data from this clinical core set can be used to compare patient characteristics of patients of other treatment setting and/or scientific publications. As treatment success might depend on case complexity, which is high in the referred patients, the advantages of earlier referral to comprehensive multidisciplinary treatment were discussed.
A detailed description of case complexity of patients with chronic pain referred for pain rehabilitation. Insight in case complexity of patients within subgroups on the basis of gender, pain duration, pain severity and pain location. These descriptions can be used as reference data for daily practice in the field of pain rehabilitation and can be used to evaluate, monitor and improve rehabilitation care in care settings nationwide as well as internationally.
Epidemiological studies on chronic pelvic pain (CPP) have focused on women of reproductive age. We aimed to determine the prevalence of chronic pelvic pain (CPP) in adult women and the differences in associated factors among women of reproductive age and older women. In addition, to determine whether distinct subgroups existed among CPP cases.
A cross-sectional postal survey was conducted among 5300 randomly selected women aged ≥25 years resident in the Grampian region, UK. Multivariable logistic regression was used to determine pregnancy-related and psychosocial factors associated with CPP. To identify subgroups of CPP cases, we performed cluster analysis using variables of pain severity, psychosocial factors and pain coping strategies.
Of 2088 participants, 309 (14.8%) reported CPP. CPP was significantly associated with being of reproductive age (odds ratios (OR) 2.43, 95% CI 1.69–3.48), multiple non-pain somatic symptoms (OR 3.58 95% CI 2.23–5.75), having fatigue (OR mild 1.74 95% CI 1.24–2.44, moderate/severe 1.82, 95% CI 1.25–2.63) and having depression (OR 1.61, 95% CI 1.09–2.38). CPP was less associated with multiple non-pain somatic symptoms in women of reproductive age compared to older women (interaction OR 0.51, 95% CI 0.28–0.92). We identified two clusters of CPP cases; those having little/no psychosocial distress and those having high psychosocial distress.
CPP is common in both age groups, though women of reproductive age are more likely to report it. Heightened somatic awareness may be more strongly associated with CPP in older women. There are distinct groups of CPP cases characterized by the absence/presence of psychosocial distress.
Heightened somatic awareness may be more strongly associated with CPP in women of post-reproductive years compared to women of reproductive years. Two subgroups of CPP cases can be differentiated by the absence/presence of psychosocial distress suggesting that stratified management approach may be more efficient.
Neuropathic pain is a debilitating condition with no adequate therapy. The health benefits of omega-3 fatty acids are established, however, the role of docosahexaenoic acid (DHA) in limiting pain has only recently been described and the mechanisms of this action remain unknown. DHA is metabolized into epoxydocosapentanoic acids (EDPs) via cytochrome P450 (CYP450) enzymes which are substrates for the soluble epoxide hydrolase (sEH) enzyme. Here, we tested several hypotheses; first, that the antinociceptive action of DHA is mediated by the EDPs. Second, based on evidence that DHA and CYP450 metabolites elicit analgesia through opioid signalling, we investigated this as a possible mechanism of action. Third, we tested whether the analgesia mediated by epoxy fatty acids had similar rewarding effects as opioid analgesics.
We tested diabetic neuropathic wild-type and sEH null mice in a conditioned place preference assay for their response to EDPs, sEHI and antagonism of these treatments with naloxone, a mu-opioid receptor antagonist.
The EDPs and sEH inhibitors were efficacious against chronic pain, and naloxone antagonized the action of both EDPs and sEH inhibitors. Despite this antagonism, the sEH inhibitors lacked reward side effects differing from opioids.
The EpFA are analgesic against chronic pain differing from opioids which have limited efficacy in chronic conditions.
EDPs and sEHI mediate analgesia in modelled chronic pain and this analgesia is blocked by naloxone. However, unlike opioids, sEHI are highly effective in neuropathic pain models and importantly lack rewarding side effects.
