Tendinopathies and Pain Sensitisation: A Meta-Analysis with Meta-Regression.

The presence of pain sensitisation has been documented and reported as being a possible cause of treatment failure and pain chronicity in several musculoskeletal conditions, such as tendinopathies. The aim of the present study is to analyse existing evidence on pain sensitisation in tendinopathies comparing the local and distant pain thresholds of healthy and affected subjects with distinct analysis for different tendinopathies. PubMed, Cochrane Central Register, Scopus, and Web Of Science were systematically searched after registration on PROSPERO (CRD42020164124). Level I to level IV studies evaluating the presence of pain sensitisation in patients with symptomatic tendinopathies, documented through a validated method, were included. A meta-analysis was performed to compare local, contralateral, and distant pain thresholds between patients and healthy controls with sub-analyses for different tendinopathies. Meta-regressions were conducted to evaluate the influence of age, activity level, and duration of symptoms on results. Thirty-four studies out of 2868 were included. The overall meta-analysis of local pressure pain thresholds (PPT) documented an increased sensitivity in affected subjects (p < 0.001). The analyses on contralateral PPTs (p < 0.001) and distant PPTs (p = 0.009) documented increased sensitivity in the affected group. The results of the sub-analyses on different tendinopathies were conflicting, except for those on lateral epicondylalgia. Patients' activity level (p = 0.02) and age (p = 0.05) significantly influenced local PPT results. Tendinopathies are characterized by pain sensitisation, but, while features of both central and peripheral sensitisation can be constantly detected in lateral epicondylalgia, results on other tendinopathies were more conflicting. Patients' characteristics are possible confounders that should be taken into account when addressing pain sensitisation.

High Prevalence of Pain Sensitization in Knee Osteoarthritis: A Meta-Analysis with Meta-Regression.

OBJECTIVE: The aim of this meta-analysis was to study the evidence on pain sensitization in knee osteoarthritis (OA), providing a quantitative synthesis of its prevalence and impact. Factors associated with pain sensitization were also investigated. METHODS: Meta-analysis; PubMed (MEDLINE), Cochrane Central Register (CENTRAL), and Web of Science were searched on February 2021. Level I to level IV studies evaluating the presence of pain sensitization in patients with symptomatic knee OA, documented through a validated method (questionnaires or quantitative sensory testing), were included. The primary outcome was the prevalence of pain sensitization. Factors influencing the prevalence were also evaluated, as well as differences in terms of pain thresholds between knee OA patients and healthy controls. RESULTS: Fifty-three articles including 7,117 patients were included. The meta-analysis of proportion documented a prevalence of pain sensitization of 20% (95% confidence interval [CI] = 16%-26%) with a significant heterogeneity of results (I2 = 89%, P < 0.001). The diagnostic tool used was the main factor influencing the documented prevalence of pain sensitization (P = 0.01). Knee OA patients presented higher pain sensitivity compared with healthy controls, both in terms of local pressure pain threshold (standardized mean difference [SMD] = -1.00, 95% CI = -1.67 to -0.32, P = 0.007) and distant pressure pain threshold (SMD = -0.54, 95% CI = -0.76 to -0.31, P < 0.001). CONCLUSIONS: Knee OA pain presents features that are consistent with a significant degree of pain sensitization. There is a high heterogeneity in the reported results, mainly based on the diagnostic tool used. The identification of the best methods to detect pain sensitization is warranted to correctly evaluate and manage symptoms of patients affected by knee OA. REGISTRATION: PROSPERO CRD42019123347.

High Rate of Pain Sensitization in Musculoskeletal Shoulder Diseases: A Systematic Review and Meta-analysis.

BACKGROUND: Pain sensitization, defined as an increased responsiveness of nociceptive neurons to normal input, is detected in several musculoskeletal diseases, but there are no systematic reviews or meta-analyses about pain sensitization in shoulder pain. OBJECTIVES: The aim of the study was to document pain sensitization rate and its impact in patients with shoulder pain. MATERIALS AND METHODS: PubMed, Cochrane Library, and Web of Science were searched on January 8, 2020. Level I-IV studies, evaluating pain sensitization in musculoskeletal shoulder disorders through validated methods (questionnaires/algometry) were included. The primary outcome was pain sensitization rate. Secondary outcomes were the pain sensitivity level measured as pressure pain threshold, temporal summation, conditioned pain modulation, and suprathreshold heat pain response. Associated demographic and psychosocial factors were evaluated. RESULTS: The rate of abnormal pressure pain threshold in patients with shoulder pain varied from 29% to 77%. Questionnaires detected pain sensitization in 11% to 24% of patients. This meta-analysis showed no difference in pressure pain threshold and central pain modulation but documented a significant difference in terms of suprathreshold heat pain response, indicating a hypersensitivity state in patients with shoulder pain versus asymptomatic controls. The only factor that was constantly found to correlate with higher sensitivity was a lower postoperative outcome. DISCUSSION: Pain sensitization has a high rate among patients with musculoskeletal shoulder pain, regardless of the specific etiology, and this may lead to worse clinical outcome after treatment of the primary disease. The best way to assess pain sensitization still needs to be identified as the assessment methods results in used high variability in the documented pain sensitization rate.

Micronized Palmitoylethanolamide: A Post Hoc Analysis of a Controlled Study in Patients with Low Back Pain - Sciatica.

BACKGROUND: Despite being widely prescribed, relatively few controlled trials have been conducted on the class of neurotrophic/antinociceptive nutraceuticals. While performing a search in the literature, we came across an old registration study on micronized palmitoylethanolamide in patients with low back pain - sciatica by Guida and colleagues. METHODS: We contacted the authors of the article and obtained all the original material, which allowed us to reanalyze the study. We assessed its clinical relevance by calculating the numbers needed to treat for pain (visual analog scale) and function (Roland-Morris Questionnaire). After excluding patients for whom the information available was insufficient, we assigned each patient to one of the five categories of increasing probability of neuropathic pain: pure lumbago, lumbago with projecting pain to surrounding regions (e.g. gluteus or groin), lumbago with projecting pain to the thigh or leg, pure sciatica and radiculopathy, and investigated any correlations (Spearman) between the improvement in pain and function with these five classes. RESULTS: Compared with placebo, palmitoylethanolamide 600 mg/die yielded a number needed to treat of 1.7 (95% confidence interval: 1.4-2) for pain, and 1.5 (95% confidence interval: 1.4-1.7) for function. The correlation between the five categories was highly significant for pain relief (P <0.0001), though not significant for reduced dysfunction. CONCLUSION: Palmitoylethanolamide was extremely effective on pain and function in a large cohort of patients with low back pain - sciatica. Although, the multiple mechanisms of action of palmitoylethanolamide are ideal for mixed pain conditions such as low back pain - sciatica, the correlation between pain relief and the likelihood of neuropathic pain suggests that this drug exerts a predominant action on the neuropathic pain component.

Chronic Pain in the Elderly with Cognitive Decline: A Narrative Review.

The presence of pain in elderly persons with cognitive decline is often neglected, under-reported, underestimated, misdiagnosed and not adequately treated, with consequences that have a strong impact on health, independence in activities of daily living and quality of life. There is no empirical evidence that people with dementia experience less pain; therefore, in patients with severe cognitive impairment the progression of cognitive decline dramatically affects the ability to verbalize the presence of pain. Self-assessment scales are considered the "gold standard" for pain assessment, but the presence of cognitive impairment is likely to reduce the reliability of these measures. Treatment of pain in elderly with cognitive decline or dementia is based on non-pharmacological and pharmacological strategies. Pharmacological treatment should consider physiological changes, high comorbidity and drug interactions that occur frequently in the elderly. This narrative review aims to describe current knowledge, methods of detection and treatment approaches for chronic pain in elderly persons with cognitive deficits.

Subjective correlates of stress management in outpatient cardiac rehabilitation: the predictive role of perceived heart risk factors.

Introduction: The causal attributions and perceived risk factors can affect patients' health behaviors. Therefore, the present study aimed to assess (i) the effect of an outpatient cardiac rehabilitation (CR) program on perceived heart risk factors (PHRFs) and on psychological stress, and (ii) the role of changes of PHRFs at pre-post CR in predicting changes in psychological stress. Methods: In this longitudinal study, 110 CR patients were assessed from June to November 2016 in a hospital in Iran. Perceived heart risk factors and perceived stress were investigated using the PHRFs scale and the Depression, Anxiety, Stress Scale-21, respectively. PHRFs and DASS-21 Stress scale scores were compared before and after 26 sessions of exercise-based CR through paired sample t-tests. In addition, we investigated the effect of PHRF's change scores on DASS-21 Stress scale scores using linear regression analysis. Results: Results showed that CR has a little impact in improving the patients' perception of heart risk factors, However, CR is significantly effective in reducing stress (P < 0.05). Regression analysis evidenced that improvements in patients' perception of risk factors can significantly predict a reduction in psychological stress (P = 0.030). The model explained 11.2% of the variance in the results. Conclusion: PHRFs appear to be significant predictive components of CR's stress reduction. Practitioners should focus on patients' perception of risk factors to facilitate stress management in CR program.

Heart rate variability during acute psychosocial stress: A randomized cross-over trial of verbal and non-verbal laboratory stressors.

Acute psychosocial stress is typically investigated in laboratory settings using protocols with distinctive characteristics. For example, some tasks involve the action of speaking, which seems to alter Heart Rate Variability (HRV) through acute changes in respiration patterns. However, it is still unknown which task induces the strongest subjective and autonomic stress response. The present cross-over randomized trial sought to investigate the differences in perceived stress and in linear and non-linear analyses of HRV between three different verbal (Speech and Stroop) and non-verbal (Montreal Imaging Stress Task; MIST) stress tasks, in a sample of 60 healthy adults (51.7% females; mean age = 25.6 ±â€¯3.83 years). Analyses were run controlling for respiration rates. Participants reported similar levels of perceived stress across the three tasks. However, MIST induced a stronger cardiovascular response than Speech and Stroop tasks, even after controlling for respiration rates. Finally, women reported higher levels of perceived stress and lower HRV both at rest and in response to acute psychosocial stressors, compared to men. Taken together, our results suggest the presence of gender-related differences during psychophysiological experiments on stress. They also suggest that verbal activity masked the vagal withdrawal through altered respiration patterns imposed by speaking. Therefore, our findings support the use of highly-standardized math task, such as MIST, as a valid and reliable alternative to verbal protocols during laboratory studies on stress.

Coronary artery bypass graft patients' perception about the risk factors of illness: Educational necessities of second prevention.

BACKGROUND: Patients' beliefs about the cause of cardiac disease (perceived risk factors) as part of the global psychological presentation are influenced by patients' health knowledge. Hence, the present study aimed to assess the relationship between actual and perceived risk factors, identification of underestimated risk factors, and indication of underestimation of every risk factor. MATERIALS AND METHODS: In this cross-sectional study, data of 313 coronary artery bypass graft (CABG) patients admitted to one hospital in the west of Iran were collected through a demographic interview, actual risk factors' checklist, open single item of perceived risk factors, and a life stressful events scale. Data were analyzed by means of Spearman's correlation coefficients and one-sample Z-test for proportions. RESULTS: Although there are significant relations between actual and perceived risk factors related to hypertension, family history, diabetes, smoking, and substance abuse (P < 0.05), there is no relation between the actual and perceived risk factors, and patients underestimate the role of actual risk factors in disease (P < 0.001). The patients underestimated the role of aging (98.8%), substance abuse (95.2%), overweight and obesity (94.9%), hyperlipidemia (93.1%), family history (90.3%), and hypertension (90%) more than diabetes (86.1%), smoking (72.5%), and stress (54.7%). CONCLUSION: Cardiac patients seem to underestimate the role of aging, substance abuse, obesity and overweight, hyperlipidemia, family history, and hypertension more than other actual risk factors. Therefore, these factors should be highlighted to patients to help them to (i) increase the awareness of actual risk factors and (ii) promote an appropriate lifestyle after CABG surgery.

Risk Factors Linked to Psychological Distress, Productivity Losses, and Sick Leave in Low-Back-Pain Employees: A Three-Year Longitudinal Cohort Study.

Background. Low back pain (LBP) is one of the most common health problems worldwide. Purpose. To investigate the link between baseline demographic and occupational, medical, and lifestyle data with following psychological and occupational outcomes in a large sample of employees with LBP over a 3-year period. Study Design. Three-year prospective cohort study. Methods. Italian-speaking employees (N = 4492) with a diagnosis of LBP were included. Screening at Time 1 was done in order to collect information about severity and classification of LBP, demographic, lifestyle, and occupational status data. Psychological distress (PGWBI) and occupational burden were assessed after 3 years. Results. After 3 years, employees with LBP not due to organic causes had an increased risk of psychological distress. Gender appears to be an important variable for following occupational burden. Indeed, being a white-collar man with a LBP without organic causes seems to be a protective factor for following work outcomes, while being a white-collar woman with a LBP not due to organic causes appears to be a risk factor for subsequent sick leave. Moreover, LBP severity affects psychological and occupational outcomes. Conclusion. Our findings have several implications that could be considered in preventive and supportive programs for LBP employees.

Non-surgical treatments for the management of early osteoarthritis.

Non-surgical treatments are usually the first choice for the management of knee degeneration, especially in the early osteoarthritis (OA) phase when no clear lesions or combined abnormalities need to be addressed surgically. Early OA may be addressed by a wide range of non-surgical approaches, from non-pharmacological modalities to dietary supplements and pharmacological therapies, as well as physical therapies and novel biological minimally invasive procedures involving injections of various substances to obtain a clinical improvement and possibly a disease-modifying effect. Numerous pharmaceutical agents are able to provide clinical benefit, but no one has shown all the characteristic of an ideal treatment, and side effects have been reported at both systemic and local level. Patients and physicians should have realistic outcome goals in pharmacological treatment, which should be considered together with other conservative measures. Among these, exercise is an effective conservative approach, while physical therapies lack literature support. Even though a combination of these therapeutic options might be the most suitable strategy, there is a paucity of studies focusing on combining treatments, which is the most common clinical scenario. Further studies are needed to increase the limited evidence on non-surgical treatments and their combination, to optimize indications, application modalities, and results with particular focus on early OA. In fact, most of the available evidence regards established OA. Increased knowledge about degeneration mechanisms will help to better target the available treatments and develop new biological options, where preliminary results are promising, especially concerning early disease phases. Specific treatments aimed at improving joint homoeostasis, or even counteracting tissue damage by inducing regenerative processes, might be successful in early OA, where tissue loss and anatomical changes are still at very initial stages.

Burden of herpes zoster-associated chronic pain in Italian patients aged 50 years and over (2009-2010): a GP-based prospective cohort study.

BACKGROUND: Post-herpetic neuralgia (PHN) is the most common complication in herpes zoster (HZ) patients. METHODS: We performed a longitudinal, prospective study in 108 general practices throughout Italy to assess how many immunocompetent patients aged ≥50 years with newly diagnosed HZ develop HZ-associated pain, its duration and management over 6-months. HZ-associated pain was assessed by a direct question to the patient and by self-assessment of the worst pain felt in the previous two weeks on a visual analogue scale (VAS), a score ≥3 was taken as pain. PHN was defined as pain reported during the study period persisting for ≥3 months. Quality of life (QoL) was measured using the SF-12 questionnaire. RESULTS: At enrolment, 370 of the 413 patients (89.6%) reported HZ-associated pain which was still present in 20.6% and 9.2% of patients after three and six months, respectively, despite many patients receiving recommended anti-viral therapy. The overall QoL scores were lower than those in healthy Italians of similar age; scores for patients with HZ-associated pain were lower. The presence of >50 vesicles and VAS score ≥3 at enrolment, and being male were significantly associated with PHN at three months. CONCLUSIONS: These results suggest that HZ and PHN represent an important burden of disease in the elderly. There is a need for interventions that can prevent and reduce the burden of HZ to help improve the quality of life of the elderly. These data may be useful as baseline epidemiology data for the assessment of the impact of the VZV vaccine in Italy, after its implementation.

Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: data from the randomized, double-blind, COMBO-DN study.

Sensory profiles are heterogeneous in neuropathic pain disorders, and subgroups of patients respond differently to treatment. To further explore this, patients in the COMBO-DN study were prospectively assessed by the Neuropathic Pain Symptom Inventory (NPSI) at baseline, after initial 8-week therapy with either duloxetine or pregabalin, and after subsequent 8-week combination/high-dose therapy. Exploratory post hoc cluster analyses were performed to identify and characterize potential subgroups through their scores in the NPSI items. In patients not responding to initial 60 mg/d duloxetine, adding 300 mg/d pregabalin for combination treatment was particularly effective regarding the dimensions pressing pain and evoked pain, whereas maximizing the duloxetine dose to 120 mg/d appeared more beneficial regarding paresthesia/dysesthesia. In contrast, adding 60 mg/d duloxetine to 300 mg/d pregabalin in case of nonresponse to initial pregabalin led to numerically higher decreases in all NPSI dimensions/items compared to maximizing the pregabalin dose to 600 mg/d. Cluster analysis revealed 3 patient clusters (defined by baseline scores for the 10 NPSI sensory items) with different pain profiles, not only in terms of overall pain severity, but also across NPSI items. Mean Brief Pain Inventory average pain improved in all clusters during combination/high-dose therapy. However, in patients with severe pain, the treatment effect showed a trend in favor of high-dose monotherapy, whereas combination therapy appeared to be more beneficial in patients with moderate and mild pain (not significant). These complementary exploratory analyses further endorse the idea that sensory phenotyping might lead to a more stratified treatment and potentially to personalized pain therapy.

Painful diabetic polyneuropathy: approach to diagnosis and management.

OBJECTIVES: To provide a current overview of the diagnostic work-up and management of painful diabetic polyneuropathy (PDPN). METHODS: A review covering the literature from 2004 to 2011, which describes the tools designed to diagnose neuropathic pain and assess its severity, including self-administered questionnaires, validated laboratory tests and simple handheld screening devices, and the evidence-based therapeutic approaches to PDPN. RESULTS: The clinical aspects, pathogenesis, and comorbidities of PDPN, as well as its impact on health related quality of life (HR-QoL), are the main drivers for the management of patients with suspected PDPN. PDPN treatment consists first of all in improving glycemic control and lifestyle intervention. A number of symptomatic pharmacological agents are available for pain control: tricyclic antidepressants and selective serotonin norepinephrine reuptake inhibitors (venlafaxine and duloxetine), α2-delta ligands (gabapentin and pregabalin), opioid analgesics (tramadol and oxycodone), and agents for topical use, such as lidocaine patch and capsaicin cream. With the exception of transcutaneous electrical nerve stimulation, physical treatment is not supported by adequate evidence. DISCUSSION: As efficacy and tolerability of current therapy for PDPN are not ideal, the need for a better approach in management further exists. Novel compounds should be developed for the treatment of PDPN.

Intrathecal therapy: what has changed with the introduction of ziconotide.

Administering drugs into the intrathecal space is becoming more popular in the treatment of patients with intractable pain or intolerable side effects of systemic analgesic treatments. Although morphine and ziconotide are the only intrathecal analgesics currently approved by regulatory authorities in the U.S. (Food and Drug Administration) and Europe (national-level approval by individual countries for morphine and European Agency for the Evaluation of Medicinal Products approval for ziconotide), a wide variety of opioid and non-opioid drugs are being used in this way. There is no official guidance concerning the selection of these drugs or their use in combinations and a paucity of efficacy and safety data from randomized controlled trials. The polyanalgesic initiative aims to summarize the current knowledge and to facilitate rational choices of intrathecal drug and drug combinations for the management of chronic pain. The most recent polyanalgesic consensus recommendations were published in 2007. In this review, we shall examine these recommendations, which are tailored toward those practicing intrathecal analgesia in the U.S., and discuss how they should be implemented in Europe, where the healthcare systems and regulations of the medical authorities are different.

Validation of the Italian version of the Neuropathic Pain Symptom Inventory in peripheral nervous system diseases.

The aim of this study was to validate the Italian version of the Neuropathic Pain Symptom Inventory (NPSI) in patients with neuropathic pain due to peripheral nerve diseases, and also to evaluate the validity of a new NPSI score: a frequency weighted NPSI score (NPSI-FW). First, the original version of the NPSI was translated into Italian. Then the validity and reliability of the Italian NPSI (I-NPSI) were tested in 392 Italian patients consecutively referred to 16 Italian outpatient services for peripheral nerve diseases, by correlating the I-NPSI scores with other pain scales. The repeatability and responsiveness were assessed. A significant correlation between the I-NPSI scores and all the other pain measures was seen. Reproducibility and responsiveness were good. Our study shows the validity of the I-NPSI and demonstrates its reliability for assessing neuropathic pain in patients with peripheral nerve diseases. The I-NPSI scores represent reliable measurements to assess neuropathic symptoms and effectiveness of treatment on them.

The Lindblom roller.

Neuropathic pain is caused by injury of the peripheral or central nervous system. The neurological examination of the sensory system in neuropathic pain patients guides the anatomical localization of the injury. Among the sensory modalities to be tested, priority should be given to those subserved by small peripheral sensory fibers or by the spinothalamic tract that most commonly are abnormal in neuropathic pain patients. Testing of cold and warm perception was traditionally carried out in the clinic using tubes filled with water at different temperatures, a cumbersome method that has limited the routine examination of these sensory modalities. The Lindblom roller offers a practical and effective method of readily testing temperature perception and is among the best available clinical tools for delineating the anatomical boundaries of a sensory abnormality. Routinely use of the Lindblom roller shall be standard bedside clinical assessment of neuropathic pain patients. To exemplify this statement we describe two patients affected by complex and fluctuating painful sensory abnormalities caused by an extradural mass compressing the spinal cord. The level of the injury was readily localized with a roller kept at room temperature.

Pre-injury lidocaine treatment prevents thermal hyperalgesia and cutaneous thermal abnormalities in a rat model of peripheral neuropathy.

The effect of lidocaine pretreatment on thermal hyperalgesia and thermal skin asymmetries provoked by experimental mononeuropathy was investigated in rats. Forty anesthetized rats were given sciatic nerve ligatures according to the technique of Bennett and Xie. Rats were divided into 3 groups: 16 were ligated without lidocaine, 16 were ligated after lidocaine bathing of the nerve, and 8 were ligated after systemic lidocaine (6-8 mg/kg). Six sham-operated rats for each group were also prepared. From the first postoperative day the responses to the hot-plate test were assessed daily for 4 weeks by tracking the paw-licking latency (PLL) for both hindpaws. Shorter or longer latencies on the operated side were respectively considered sign of hyperalgesia and hypoalgesia. Infrared thermographic images of plantar hindpaws were taken in 22 operated rats in the 2nd postoperative week. Thermographic images of 8 non-operated rats were used as control. Animals operated without lidocaine exhibited shorter PLL (P < 0.001) and a decreased skin temperature on the operated side (P < 0.001). In the lidocaine-pretreated rats, no paw-licking reflex was present for a variable postoperative period (1 week or more) and afterwards there was a trend toward recovery of normal PLL values at the 4th week; the hindpaw skin temperature was symmetrical and normal. Sham-operated rats had normal tests. It is postulated here that lidocaine prevents behavioral and thermal manifestation of mononeuropathy by blocking early afferent injury barrage.

Interactions between sympathetic vasoconstrictor outflow and C nociceptor-induced antidromic vasodilatation.

The interaction between orthodromic sympathetic vasoconstrictor and antidromic vasodilator effects of C-fiber stimulation was studied in normal human volunteers. Excitation of C fibers was achieved through administration of intermittent painful intraneural microstimulation to upper limb nerves, while recording cutaneous thermal emission profiles in the projected fields of cutaneous sensation. During initial stimulation, when both systems are co-activated, skin temperature decreased. Temperature increased after termination of the stimulus. Eventually, temperature decreased again upon renewed stimulation. Thus, sympathetic vasoconstriction was found to override the antidromic vasodilator effect induced by stimulation of C nociceptors. When interpreting abnormal deviations of skin temperature in patients with peripheral nerve disorders, the dynamic interplay between opposing vasomotor effects driven by sympathetic and somatic systems must be taken into consideration.