Volume 18, Issue 1

Background and aims: Treatment of pain following major limb amputations is often a clinical challenge in a patient population consisting mainly of elderly with underlying diseases. Literature on management of acute post-amputation pain is scarce. We performed a systematic review on this topic to evaluate the efficacy and safety of analgesic interventions for acute pain following major limb amputation. Methods: A literature search was performed in PubMed, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews using the following key words: [(amputation) AND (pain OR analgesi* OR pain relief)] AND (acute OR postoperative). Randomized controlled studies (RCTs) and observational studies investigating treatment of acute pain following major amputations for any indication (peripheral vascular disease, malignant disease, trauma) were included. The review was performed according to the standards described in the PRISMA statement. The Cochrane quality assessment tool was used to evaluate the risk of bias in the RCTs. Results: Nineteen studies with total of 949 patients were included. The studies were generally small and heterogeneous on outcomes, study designs and quality. There were 16 studies on epidural or continuous perineural analgesia (CPI). Based on five RCTs ( n =268) and two observational studies ( n =49), epidural analgesia decreased the intensity of acute stump pain as compared to systemic analgesics, during the first 24 h after the operation. Based on one study epidural analgesia caused more adverse effects like sedation, nausea and motor block than continuous perineural local anesthetic infusion. Based on one RCT ( n =21) and eight observational studies ( n =501) CPI seemed to decrease opioid consumption as compared to systemic analgesics only, on the first three postoperative days, and was well tolerated. Only three trials investigated systemic analgesics (oral memantine, oral gabapentine, iv ketamine). Ketamine did not decrease acute pain or opioid consumption after amputation as compared to other systemic analgesics. Gabapentin did not decrease acute pain when combined to epidural analgesia as compared to epidural analgesia and opioid treatment, and caused adverse effects. Conclusions: The main finding of this systematic review is that evidence regarding pain management after major limb amputation is very limited. Epidural analgesia may be effective, but firm evidence is lacking. Epidural causes more adverse effects than CPI. The results on efficacy of CPI are indecisive. The data on adjuvant medications combined to epidural analgesia or CPI is limited. Studies on efficacy and adverse effects of systemic analgesics for amputation pain, especially concentrating on elderly patients, are needed.

Background and aims: Acute pain episodes associated with sickle cell disease (SCD) are very difficult to manage effectively. Opioid tolerance and side effects have been major roadblocks in our ability to provide these patients with adequate pain relief. Ketamine is cheap, widely safe, readily available drug, with analgesic effects at sub-anesthetic doses and has been used in wide range of surgeries, pediatric burns dressing change and cancer related pain however, literature concerning its use in sickle cell crises is still limited in our setting. This study aimed to establish if 1 mg/kg of intravenous ketamine is non inferior to intravenous morphine 0.1 mg/kg in severe SCD-associated pain. Methods: We performed an institutional review board-approved randomized, prospective, double-blinded, active-control, non-inferiority trial at the national referral sickle cell center. Children between 7 and 18 years of age with severe painful sickle cell crisis, defined by numerical rating scale score of greater or equal to 7 were enrolled. Patients were consented and randomized to receive, either IV ketamine (LDK) 1 mg/kg or IV morphine (MOR) 0.1 mg/kg as an infusion over 10 min. The primary endpoint is maximal change in Numerical Rating Scale (NRS) pain score. Secondary outcomes were, incidence of adverse effects, optimal time to and duration of action of ketamine and incidence of treatment failures by treatment group. A clinically meaningful difference in validated pain scores was defined as 1.3 units. Assuming both treatments are on average equal, a sample size of 240 patients (120 per group) provided 95% power to demonstrate that IV LDK is non-inferior to IV morphine with a 0.05 level of significance and a 10% non-inferiority margin. All analyses were based on a modified intention to treat. This trial was registered with clinicaltrials.gov NCT02434939. Results: Two hundred and forty patients were enrolled (LDK120, MOR120). Demographic variables and baseline NRS scores (8.9 vs. 9.2) were similar. LDK was comparable to MOR in the maximum change in NRS scores, 66.4% vs. 61.3% (MD 5.5; 95% CI −2.2 to −13.2). Time to achieve maximum reduction in NRS pain scores was at 19.8 min for LDK and 34.1 min for MOR. The average duration of action for LDK was 60 min. MOR had more patients still at maximum effect at 120 min (45.8% vs. 37.5%; RR 1.2; 95% CI 0.9–1.7). LDK patients were 11.3 times more likely to develop side effects, though were transient, anticipated and non-life threatening (37.5% vs. 3.3%). MOR had significantly more treatment failures 40% vs. 28.3% (RR 0.7; 95% CI 0.5–1.03, p =0.07) Vital signs and sedation scores were similar in both groups. Conclusions: Intravenous LDK at 1 mg/kg provides comparable analgesic effectiveness as IV MOR in the acute treatment of severe painful sickle cell crisis in children in the day care sickle cell center. However, it is associated with a high incidence of several transient, non-life threatening mild side effects. Implications: Intravenous ketamine at 1 mg/kg can be a reliable alternative to morphine in the management of severe painful sickle cell crisis especially in a resource limited area where morphine is not readily available.

Background and aims: Current therapies for persistent complex regional pain syndrome (CRPS) are grossly inadequate. With accruing evidence to support an underlying immunological process and anecdotal evidence suggesting potential efficacy of mycophenolate, we wished to explore the feasibility and effectiveness of this treatment in patients with CRPS. Methods: A randomised, open, parallel, proof of concept trial was conducted. Patients with Budapest research criteria CRPS of >2-year duration and moderate or high pain intensity (numeric rating scale score ≥5) were enrolled. Eligible patients were randomised 1:1 to openly receive mycophenolate as add-on treatment, or their usual treatment alone, over 5.5 months. They then switched to the other treatment arm for 5.5 months. The main outcome was average the patients’ average pain intensity recorded over 14 days, between 5.0 and 5.5 months post randomisation, on 11-point (0–10) numeric rating scales, compared between trial arms. Skin sensitivities and additional outcomes were also assessed. Results: Twelve patients were enrolled. Nine provided outcomes and were analysed for the main outcome. Mycophenolate treatment was significantly more effective than control [drug-group mean (SD): pre: 7.4 (1.2)- post: 5.2 (1.3), n =4, control: pre: 7.7 (1.4)- post: 8.1 (0.9), n =5; −2.8 (95% CI: −4.7, −1.0), p =0.01, analysis of covariance]. There were four treatment responders (to mycophenolate treatment either before, or after switch), whose initial exquisite skin hyper-sensitivities, function and quality of life strongly improved. Side effects including itchiness, skin-cryptitis, increased pain, and increased depression caused 45% of the subjects to stop taking mycophenolate. Conclusions: Mycophenolate appears to reduce pain intensity and improve quality of life in a subgroup of patients with persistent CRPS. Implications: These results support the feasibility of conducting a definite trial to confirm the efficacy and effect size of mycophenolate treatment for persistent CRPS (EudraCT 2015-000263-14).

Background and aims: Knowledge of pain characteristics among the healthy population or among people with minimal pain-related disability could hold important insights to inform clinical practice and research. This study investigated pain prevalence among healthy individuals and compared psychosocial and physical characteristics between adults with and without pain. Methods: Data were from 1,000 self-reported healthy participants aged 3–101 years (1,000 Norms Project). Single-item questions assessed recent bodily pain (“none” to “very severe”) and chronic pain (pain every day for 3 months in the previous 6 months). Assessment of Quality of Life (AQoL) instrument, New Generalised Self-Efficacy Scale, International Physical Activity Questionnaire, 6-min walk test, 30-s chair stand and timed up-and-down stairs tests were compared between adults with and without pain. Results: Seventy-two percent of adults and 49% of children had experienced recent pain, although most rated their pain as mild (80% and 87%, respectively). Adults with recent pain were more likely to be overweight/obese and report sleep difficulties, and had lower self-efficacy, AQoL mental super dimension scores and sit-to-stand performance, compared to adults with no pain ( p <0.05). Effect sizes were modest (Cohen’s d =0.16–0.39), therefore unlikely clinically significant. Chronic pain was reported by 15% of adults and 3% of children. Adults with chronic pain were older, more likely to be overweight/obese, and had lower AQoL mental super dimension scores, 6-min walk, sit-to-stand and stair-climbing performance ( p <0.05). Again, effect sizes were modest (Cohen’s d =0.25–0.40). Conclusions: Mild pain is common among healthy individuals. Adults who consider themselves healthy but experience pain (recent/chronic) display slightly lower mental health and physical performance, although these differences are unlikely clinically significant. Implications: These findings emphasise the importance of assessing pain-related disability in addition to prevalence when considering the disease burden of pain. Early assessment of broader health and lifestyle risk factors in clinical practice is emphasised. Avenues for future research include examination of whether lower mental health and physical performance represent risk factors for future pain and whether physical activity levels, sleep and self-efficacy are protective against chronic pain-related disability.

Background and aims: Individuals with non-acute pain are challenged with variable pain responses following surgery as well as psychological challenges, particularly depression and catastrophizing. The purpose of this study was to compare pre- and postoperative psychosocial tests and the associated presence of sensitization on a cohort of women undergoing elective laparoscopic surgery for non-acute pain defined as pain sufficient for surgical investigation without persistent of chronic pain. Methods: The study was a secondary analysis of a previous report (Am J Obstet Gynecol 2014 Oct;211(4):360–8.). The study was a prospective cohort trial of 77 women; 61 with non-acute pain and 16 women for a tubal ligation. The women had the following tests: Pain Disability Index, Pain Catastrophizing Scale, CES-D (Center for Epidemiologic Studies Depression Scale) depression scale and the McGill Pain Scale (short form) as well as their average pain score and the presence of pain sensitization. All test scores were correlated together and comparisons were done using paired t -test. Results: There were reductions in pain and psychosocial test scores that were significantly correlated. Pre-operative sensitization indicated greater changes in psychosocial tests. Conclusions: There was a close association of tests of psychosocial status with average pain among women having surgery on visceral tissues. Incorporation of these tests in the pre- and postoperative evaluation of women having laparoscopic surgery appears to provide a means to a broader understanding of the woman’s pain experience.

Background and aims: Amplification of sensory signalling within the nervous system along with psychosocial factors contributes to the variation and severity of knee pain. Quantitative sensory testing (QST) is a non-invasive test battery that assesses sensory perception of thermal, pressure, mechanical and vibration stimuli used in the assessment of pain. Psychosocial factors also have an important role in explaining the occurrence of pain. The aim was to determine whether QST measures were associated with self-reported pain, and whether those associations were mediated by psychosocial factors. Methods: Participants with knee pain identified from a population-based cohort completed a tender point count and a reduced QST battery of thermal, mechanical and pressure pain thresholds, temporal summation, mechanical pain sensitivity (MPS), dynamic mechanical allodynia (DMA) and vibration detection threshold performed following the protocol by the German Research Network on Neuropathic Pain. QST assessments were performed at the most painful knee and opposite forearm (if pain-free). Participants were asked to score for their global and knee pain intensities within the past month (range 0–10), and complete questionnaire items investigating anxiety, depression, illness perceptions, pain catastrophising, and physical functioning. QST measures (independent variable) significantly correlated (Spearman’s rho) with self-reported pain intensity (dependent variable) were included in structural equation models with psychosocial factors (latent mediators). Results: Seventy-two participants were recruited with 61 participants (36 women; median age 64 years) with complete data included in subsequent analyses. Tender point count was significantly correlated with global pain intensity. DMA at the knee and MPS at the most painful knee and opposite pain-free forearm were significantly correlated with both global pain and knee pain intensities. Psychosocial factors including pain catastrophising sub-scales (rumination and helplessness) and illness perceptions (consequences and concern) were significant partial mediators of the association with global pain intensity when loaded on to a latent mediator for: tender point count [75% total effect; 95% confidence interval (CI) 22%, 100%]; MPS at the knee (49%; 12%, 86%); and DMA at the knee (63%; 5%, 100%). Latent psychosocial factors were also significant partial mediators of the association between pain intensity at the tested knee with MPS at the knee (30%; 2%, 58%), but not for DMA at the knee. Conclusions: Measures of mechanical hyperalgesia at the most painful knee and pain-free opposite forearm were associated with increased knee and global pain indicative of altered central processing. Psychosocial factors were significant partial mediators, highlighting the importance of the central integration of emotional processing in pain perception. Implications: Associations between mechanical hyperalgesia at the forearm and knee, psychosocial factors and increased levels of clinical global and knee pain intensity provide evidence of altered central processing as a key mechanism in knee pain, with psychological factors playing a key role in the expression of clinical pain.

Background and aims: The association between different types of physical activity and fear-avoidance beliefs remains unclear. This study investigates the association between work-related and leisure-time physical activity with fear-avoidance beliefs in the general working population. Methods: Currently employed wage earners ( n =10,427) from the 2010 round of the Danish Work Environment Cohort Study replied to questions about work, lifestyle and health. General linear models controlling for lifestyle, psychosocial work factors, education, pain, medication-use and chronic diseases tested associations of work-related and leisure-time physical activity (explanatory variables) with fear-avoidance beliefs (outcome variable, scale 0–100). Results: The level of fear-avoidance was 41.7 (SD 27.3), 38.0 (SD 26.9) and 54.3 (SD 27.7) among the general working population, a subgroup of pain-free individuals, and a subgroup with back disease, respectively. In the general working population, the level of fear-avoidance among those with low, moderate and high physical activity during leisure were 47 [95% confidence intervals (CI) 45–49], 44 (95% CI 42–46) and 43 (95% CI 41–45), and physical activity at work were 40 (95% CI 39–42), 44 (95% CI 42–46) and 49 (95% CI 48–51), respectively. Individuals with back disease and a high level of physical activity at work showed the overall highest level of fear-avoidance whereas pain-free individuals with a low level of physical activity at work showed the overall lowest level of fear-avoidance. Conclusions: Physical activity during work and leisure shows contrasting associations with fear-avoidance beliefs. While high physical activity during leisure is associated with lower levels, high physical activity at work is associated with higher levels of fear-avoidance. Implications: The present results may reflect some deeply rooted negative beliefs about pain and work in the population. On the societal level, campaigns may be a possible way forward as these have shown to improve beliefs about musculoskeletal pain and work.

Background and aims: Irritable bowel syndrome (IBS), is a common multifactorial gastrointestinal disorder linked to disturbances in the microbe gut-brain axis. Cognitive behavioral therapy (CBT), in face-to-face format has showed promising results on IBS and its associated psychological symptoms. The present study explored for the first time if CBT for IBS affects the autonomic nervous system (ANS) during experimentally induced visceral pain and cognitive stress, respectively. The levels of state and trait anxiety, current and perceived stress were also evaluated. Methods: In this uncontrolled trial, individual CBT was performed in face-to-face format for 12 weeks in 18 subjects with IBS. Heart rate variability and skin conductance were measured during experimentally induced visceral pain and during a cognitive task (Stroop color-word test), before and after intervention. The levels of state and trait anxiety as well as self-rated current and perceived stress were also measured before and after the intervention. Results: CBT did not affect ANS activity during experimentally induced visceral pain and cognitive stress. The sympathetic activity was high, typical for IBS and triggered during both visceral pain and cognitive stress. The levels of state and trait anxiety significantly decreased after the intervention. No significant changes in self-rated current or perceived stress were found. Conclusions: Results suggest that face-to-face CBT for IBS improved anxiety- a key psychological mechanism for the IBS pathophysiology, rather than the autonomic stress response to experimentally induced visceral pain and cognitive stress, respectively. Implications: This study indicates that IBS patients present high levels of stress and difficulties coping with anxiety and ANS activity during visceral pain and a cognitive stress test, respectively. These manifestations of IBS are however not targeted by CBT, and do not seem to be central for the study participants IBS symptoms according to the current and our previous study. Face-to-face CBT for IBS, it does not seem to affect modulation of ANS activity in response to induced visceral pain or cognitive stress. Instead, face-to-face CBT decreased levels of state and trait anxiety. Implications for further studies include that anxiety seems to be important in the IBS pathophysiology, and needs further scientific attention. This is in line with the fear-avoidance model which suggests that anxious responses to pain and discomfort drive hypervigilance to, and (behavioral) avoidance of, symptom provoking stimuli and vice versa. Catastrophic cognitions, hypervigilance and avoidant behavioral responses are proposed to produce vicious circles that withhold and exacerbate pain-related symptoms and disability, and lead to lower quality of life. Larger scale studies of potential autonomic changes are needed in order to elucidate which mechanisms elicit its effects in face-to-face CBT for IBS, and provide new avenues in understanding the pathophysiology of IBS.

Background and aims: Matrix metalloproteinase 9 (MMP9) is an enzyme that may affect degradation of several extracellular matrix (ECM) components in the pelvic ligaments during pregnancy. Previous studies indicate that genetic variations in the gene encoding MMP9 may affect the enzymatic activity. One such genetic variant is a single nucleotide polymorphism (SNP), rs17576 A>G. In this study we investigated whether the MMP9 SNP rs17576 A>G may be associated with increased lumbopelvic pain in 838 pregnant woman. The study was registered with ClinicalTrials.gov (NCT 00476567) on May 21, 2007. Methods: Lumbopelvic pain-intensity was measured by visual analog scale (VAS) at two time points during pregnancy, T1 (18–22 weeks), T2 (32–36 weeks) and 3 months after delivery. Blood samples were collected at each point and SNP genotyping was carried out using predesigned TaqMan SNP genotyping assays. Results: The results showed a significant association between the number of G alleles and pain-intensity in the evening at T2. The pain among G/G carriers was higher than among A/G carriers, which in turn was higher than among the A/A carriers. The most pronounced association between the G allele and pain-intensity was observed in primiparae. Conclusions: We conclude that the MMP9 rs17576 A>G polymorphism is associated with increased lumbopelvic pain-intensity during pregnancy. The present data support the hypothesis that lumbopelvic pain during pregnancy may be related to a relaxin – MMP9 – tissue remodeling mechanism. Implications: The present findings may be important for future mechanistic studies on how MMP9 rs17576 A>G may affect changes in the ECM components in pelvic ligaments and lumbopelvic pain-intensity during pregnancy.

Background and aims: The Numerical Rating Scale (NRS), Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), and Faces Pain Scale-Revised (FPS-R) are valid measures of pain intensity. However, ratings on these measures may be influenced by factors other than pain intensity. The purpose of this study was to evaluate the influence of non-pain intensity factors on the pain intensity scales. Methods: We administered measures of pain intensity (NRS, VAS, VRS, FPS-R), pain unpleasantness, catastrophizing, depressive symptoms, and pain interference to 101 individuals with chronic lower back or knee pain. Correlation analyses examined the associations among the pain intensity scales, and regression analyses evaluated the contributions of the non-pain intensity factors (depressive symptoms, and pain unpleasantness, catastrophizing, and interference) to the VAS, VRS, and FPS-R ratings, while controlling for NRS, age, and gender. Results: Although the NRS, VAS, VRS, FPR-S, scales were strongly associated with one another, supporting their validity as measures of pain intensity, regression analyses showed that the VRS also reflected pain interference, the FPS-R also reflected pain unpleasantness, and the VAS was not associated with any of the additional non-pain intensity factors when controlling for NRS, age, and gender. Conclusions: The VAS appears to be most similar to the NRS and less influenced by non-pain intensity factors than the VRS or FPS-R. Although the VRS and FPS-R ratings both reflect pain intensity, they also contain additional information about pain interference and pain unpleasantness, respectively. These findings should be kept in mind when selecting pain measures and interpreting the results of research studies using these scales. Implications: The influence of pain interference and pain unpleasantness on VRS and FPS-R, respectively should be kept in mind when selecting pain measures and interpreting the results of research studies using these scales.

Background and aims: Suspending an ongoing activity with the intention to resume it again later is a natural response to pain. This response facilitates coping with the pain, but it may also have negative consequences for the resumption and performance of the activity. For example, people with pain problems are often forced to take a break from doing their household chores because of their pain. They might delay resuming their chore, eventually needing longer time to finish it. We investigated how activity interruptions by pain influence the pattern of subsequent activity performance. We expected that when an activity is interrupted by pain (compared to non-pain), people spend longer time away from the activity, need longer time to complete it, and are less motivated to perform it. Methods: Sixty healthy volunteers performed an ongoing task that required them to make joystick movements in different directions according to a specific rule. Occasionally, participants received either a painful electrocutaneous stimulus or a non-painful and non-aversive auditory stimulus (between-subjects) as an interruption cue. The interruption cue was followed by the temporary suspension of the ongoing task and the initiation of a different activity (interruption task). The latter required the categorization of cards and had a maximum duration, but participants could also stop it earlier by pressing a button. We measured time away from the (interrupted) ongoing task, total time to complete the ongoing task (including the interruptions) and self-reported motivation to perform both the ongoing as well as the interruption task. Results: Groups did not differ in the time away from the ongoing task, total time to complete the ongoing task, or self-reported motivation to perform the two tasks. Conclusions: Activity interruptions by pain did not impair the pattern of activity performance more than activity interruptions by non-pain. Potential explanations and suggestions for future research are discussed. Implications: Interrupting ongoing activities is a common response to pain. However, activity interruptions by pain do not appear to influence the pattern of activity performance in a different way than activity interruptions by pain-irrelevant external stimuli.

Background: Chronic pain conditions are associated with neuroplasticity within the central nervous system. In most patients the maladaptive consequence of neuroplasticity supports prolonged course of chronic pain, despite the absence of a commensurate etiology. From a pain neuromatrix perspective it can involve three different circuits within the central nervous system; the classical sensory pathway, the limbic system pathway, and the associative pathways involving the parietal cortical connections. Although this can be conceptualized as a fluid system composed of several interacting networks, it can be broadly separated into a nociceptive specific network of spino-thalamic neurons and second order neurons beyond thalamus that are not nociceptor specific. Thalamus acts as an important relay station that conveys nociceptive signaling to higher centres. Neuroplastic changes can potentially involve any parts within this neuromatrix. It is very uncommon to observe the sudden disappearance of such a chronic pain condition. Methods and results: In this case report, the author describes the clinical course of a patient with severe chronic low back pain (CLBP), whose pain suddenly disappeared after a stroke involving his left thalamus. Although extremely rare, existing case reports of such disappearance of pain with a secondary stroke in patients suffering from central post stroke pain (CPSP) are reviewed. The author further postulates hypotheses that could potentially explain this phenomenon based on the existing knowledge. Conclusions and implications: Although extremely rare and unpredictable, a thalamic stroke involving areas that are involved in chronic pain signaling can potentially lead to disappearence of an existing chronic pain condition. This is the first case report of such sudden disappearence of CLBP with well established nociceptive pathology supported by clinical and imaging findings. This unique case report could potentially generate ideas for future research and clinical treatment in the field of neuromodulation and brain stimulation.

Schwannoma is a common neoplasm in the peripheral and central nervous systems. Sciatic nerve schwanommas are rare. We report the case of a 50-year-old woman who was referred for treatment of persistent neuropathic pain in the left lower limb after resection of a schwannoma on the left S1 nerve root. The patient’s history goes back when she was 27 years old and started to have electric-like pain in her lower left limb upon intercourse. Examination revealed a left ovarian cyst which was surgically removed. Her pain persisted despite taking nonsteroidal anti inflammatory drugs (NSAIDs). Several years later a schwannoma on the left S1 nerve root was detected. The patient had surgical excision of the left S1 nerve root at the plexus along with the schwannoma. Following the surgery, she experienced pain upon sitting and touch, and had a limp in her left leg. She was prescribed NSAIDs, antidepressant and pregabalin. Despite the pharmacological treatment, the patient had persistent mild pain. Upon physical examination, the incision from her previous surgery was 4 cm away from the sacral midline and parallel to S1 and S2. The length of the incision was 3 cm. The patient had severe allodynia upon palpation at the area between S1 and L5 and the visual analog scale (VAS) score increased from 3 to 10. She had severe pain at rest and movement. Her neurologic exam revealed that the left lower extremity motor power showed mild weakness in the leg abduction, foot eversion, plantar and toes flexion, and in the hip extension. The sensory exam showed severe reduction in pinprick and temperature sensation in the lateral aspect of foot, lower leg and dorsolateral thigh and buttocks. Nerve stimulator guided injection was performed at the pain trigger point being 1 cm above the midline of the incision. Upon nerve stimulation the contraction of the gluteal muscle was observed . Then, 20 mL of the anesthetic mixture were injected. The patient had immediate pain relief after the block (VAS 1/10). She remained pain free for 15 days after which pain reappeared but with less severity (3/10). Repetitive sciatic nerve block was performed in a progressive manner and was shown to be effective in managing neuropathic pain.