Volume 5, Issue 4

Background and aim “Gain-of-function” mutations in voltage-gated sodium channel Na V 1.7 have been linked to erythromelalgia (EM), characterized by painful hot and red hands and feet. We investigated the proportion of patients with EM that carry a mutation in Na V 1.7 or in other pain-related genes and studied possible clinical differences. Methods In this study, 48 patients with EM were screened for mutations in a total of 29 candidate genes, including all sodium channel subunits, transient receptor potential channels (TRPA1, TRPV1, TRPM8), neurotrophic factors (NGF, NGFR, BDNF, GDNF, NTRK1 and WNK1) and other known pain-related genes (CACNG2, KCNS1, COMT, P2RX3, TAC1, TACR1), using a combination of next generation sequencing and classical Sanger sequencing. Results In 7/48 patients protein-modifying mutations of Na V 1.7 (P187L, I228M, I848T ( n = 4) and N1245S) were identified. Patients with the I848T mutation could be identified clinically based on early onset and severity of the disease. In contrast, there were no clinical characteristics that differentiated the other patients with Na V 1.7 mutation from those patients without. We also found more than twenty rare protein-modifying genetic variants in the genes coding for sodium channels (Na V 1.8, Na V 1.9, Na V 1.6, Na V 1.5, Na V 2.1, SCN1B, SCN3B), transient receptor potential channel (TRPA1, TRPV1), and other pain-related targets (WNK1 and NGFR). Conclusion We conclude that functionally characterized mutations of Na V 1.7 (I848T) are present only in a minority of patient with EM. Albeit the majority of patients (27/48) carried rare protein-modifying mutations the vast majority of those will most probably not be causally linked to their disease. Implications The key question remaining to be solved is the possible role of rare variants of Na V 1.8, Na V 1.9, or beta-subunits in provoking chronic pain conditions or even EM.

Background Chronic whiplash-associated disorders (WADs) are often associated with social functioning problems and decreased ability to perform previous activities. This may lead to decreased life satisfaction, which is insufficiently studied in the context of whiplash injuries. Symptoms included in chronic WAD are similar to symptoms frequently reported by persons who have sustained mild traumatic brain injury (MTBI)/concussion. In cases of MTBI, the severity and number of symptoms have been suggested to have a diagnostic value. The corresponding importance of symptoms in chronic WAD has not been documented. Most studies of whiplash injuries have focused on neck pain because this is the dominant complaint, while other symptoms are less studied. The frequency of long-term symptoms after whiplash injuries seems to vary. It is difficult to compare the long-term outcome since the follow-up after whiplash injury in most studies has been rather short. Therefore, the primary aim of this investigation was to study neck pain and other symptoms, disability, and life satisfaction five years after whiplash injury in a defined population and geographical area. Methods The study was carried out at a public hospital in northern Sweden and was a cross-sectional survey of patients five years after the injury event in a cohort of whiplash-injured patients. Five years after the emergency department visit, 186 persons aged 18–64 answered questionnaires on symptoms (Rivermead Post-Concussion Symptoms Questionnaire, RPQ), disabilities (Rivermead Head Injury Follow Up Questionnaire, RHFUQ), and life satisfaction (LiSat-11). The answers were compared to those of a comparison cohort. Results The most common symptoms five years after whiplash injury were fatigue (41%), poor memory (39%), and headache (37%). Inability to sustain previous workload (44%) and fatigue at work (43%) were frequently reported disabilities. Only 39% were satisfied with their somatic health and 60% with their psychological health. Compared with healthy controls, the whiplash injured exhibited more symptoms and had lower life satisfaction. Women reported significantly higher pain intensity than men. Few significant differences between women and men regarding the other parameters were found. Conclusions This study shows that five years after a whiplash injury, patients reported symptoms that are typical of mild traumatic brain injury. Further, this study emphasizes the possibility of screening patients with chronic WAD for these symptoms as a complement to the assessment. Implications Untreated symptoms may negatively affect the outcome of pain rehabilitation. This implies that it might be clinically meaningful to quantify symptoms earlier in the rehabilitation process

Background and aims Thoracotomies can cause severe pain, which persists in 21–67% of patients. We investigated whether NSAID + intravenous patient-controlled analgesia (IV-PCA) with morphine is an efficacious alternative to thoracic epidural analgesia (TEA). We also wanted to find out whether an extended controlled pain management protocol within a clinical study can decrease the incidence of persistent post-thoracotomy pain. Methods Thirty thoracotomy patients were randomized into 3 intervention groups with 10 patients in each. G1: preoperative diclofenac 75mg orally+150 mg/24h IV for 44h, then PO; G2: valdecoxib 40mg orally+parecoxib 80mg/24h IV for 44h, then PO. IV-PCA morphine was available in groups 1 and 2 during pleural drainage, and an intercostal nerve block at the end of surgery was performed; G3: parac-etamol+patient controlled epidural analgesia (PCEA) with a background infusion of bupivacaine with fentanyl. After PCA/PCEA oxycodone PO was provided when needed. These patients were contacted one week, 3 and 6 months after discharge. Patients ( N = 111) not involved in the study were treated according to hospital practice and served as a control group. The control patients’ data from the perioperative period were extracted, and a prospective follow-up questionnaire at 6 months after surgery similar to the intervention group was mailed. Results The intended sample size was not reached in the intervention group because of the global withdrawal of valdecoxib, and the study was terminated prematurely. At 6 months 3% of the intervention patients and 24%ofthe control patients reported persistent pain ( p <0.01). Diclofenac and valdecoxib provided similar analgesia, and in the combined NSAID group (diclofenac+valdecoxib) movement-related pain was milder in the PCEA group compared with the NSAID group. The duration of pain after coughing was shorter in the PCEA group compared with the NSAID+IV-PCA group. The only patient with persistent painat6 months postoperatively had a considerably longer duration ofpain after coughing than the other Study patients. The patients with mechanical hyperalgesia had more pain on movement. Conclusions Both PCEA and NSAID+IV-PCA morphine provided sufficient analgesia with little persistent pain compared with the incidence of persistent pain in the control group. High quality acute pain management and follow-up continuing after discharge could be more important than the analgesic method per se in preventing persistent post-thoracotomy pain. In the acute phase the measurement of pain when coughing and the duration of pain after coughing could be easy measures to recognize patients having a higher risk for persistent post-thoracotomy pain. Implications To prevent persistent post-thoracotomy pain, the extended protocol for high quality pain management in hospital covering also the sub-acute phase at home, is important. This study also provides some evidence that safe and effective alternatives to thoracic epidural analgesia do exist. The idea to include the standard “as usual” care patients as a control group and to compare them with the intervention patients provides valuable information of the added value of being a study patient, and deserves further consideration in future studies.

Background and aims We have previously reported that systemic administration of sinomenine produced antinociception in various experimental pain conditions in rodents, particularly in models of neuropathic pain. In the present study we assessed the effects of repeated administration of sinomenine in two rodent models of neuropathic pain in order to study the development of tolerance. Methods The analgesic effect of sinomenine was tested in female Sprague-Dawley rats that exhibited mechanical and cold hypersensitivity following ischaemic injury to the spinal cord and in male C57/BL6 mice that developed mechanical hypersensitivity after ischaemic injury to the sciatic nerve. Briefly, the animals were anaesthetized and injected i.v. with the photosensitizing dye erythrosine B. Vertebral segments T12 to T13 in rats or the sciatic nerve in mice were exposed and irradiated under an argon ion laser for 10min or 45s, respectively. In rats, mechanical hypersensitivity to pressure with von Frey hairs, the response to brushing and decreasing cold temperature were tested in the flanks or upper back areas. In mice, mechanical hypersensitivity on the hind paw to von Frey hairs and response to cold following a drop of acetone were measured. Sinomenine was administered i.p. in rats and p.o. in mice at 10:00 and 16:00, twice a day for 5 days. Response threshold before and 2h after drug administration at 10.00h was recorded. Results Repeated administration of sinomenine at 10 or 20mg/kg twice a day, doses that have no analgesic effect as single injection, alleviated mechanical, but not cold allodynia in spinally injured rats and the effect was maintained during the 5 day treatment period with no signs of tolerance. Furthermore, the pre-drug response threshold was significantly elevated during repeated treatment with 20mg/kg sinomenine. Sinomenine administered at 40mg/kg twice a day for 5 days significantly reduced mechanical and cold alldoynia, elevated pre-drug response threshold without tolerance development in spinally injured rats. Similarly, sinomenine at 80mg/kg twice a day for 5 days significantly reduced mechanical allodynia in mice with sciatic nerve injury and increased pre-drug response threshold with no sign of tolerance. The effect of sinomenine on response threshold persisted for days after termination of the 5 day drug administration. Conclusions The results suggest that repeated administration of simomenine produced an enhanced anti-allodynic effect without tolerance in rodent models of neuropathic pain. Implications Sinomenine may be tested as a novel analgesic in treating some forms of chronic neuropathic pain in patients.

Background and aims The ultraviolet-B (UVB) inflammatory model is a well-established model of inflammatory pain. This study investigated whether UVB-induced cutaneous inflammation would enhance pain responses from the underlying deep somatic areas. Methods Skin inflammation was induced, in 24 healthy volunteers, by UVB irradiation (three times of the individual minimal erythema UVB dose) in square-shaped areas on the forearm and lower back. Assessments of cutaneous blood flow, pin-prick thresholds, pressure pain thresholds and tolerance, stimulus–response functions relating graded pressure stimulations and pain intensity (visual analogue scale, VAS) were performed within and outside the irradiated area. Results Twenty-four hours after UVB irradiation, a significant increase in superficial blood flow in the irradiated skin area was demonstrated compared with baseline ( P < 0.01) indicating that inflammation was induced. Compared with baseline, UVB irradiation significantly reduced the pin-prick thresholds, pressure pain thresholds and tolerance within and outside of the irradiated area ( P < 0.05). The stimulus–response function was left-shifted compared with baseline both within and outside the irradiated area ( P < 0.05) with a more pronounced left-shift within the irradiated area ( P < 0.01). Application of topical anaesthesia 24h after irradiation in 5 subjects, both within and outside the irradiated area, could only increase the pin-prick thresholds outside the irradiated area. Conclusion The UVB irradiation of the skin not only provokes cutaneous primary and secondary hyper-algesia but also causes hyperalgesia to blunt pressure stimulations 24h after the UVB exposure. Implications The presented UVB model can be used as a translational model from animals into healthy subjects. This model can potentially be used to screen drug candidates with anti-inflammatory properties in early stages of drug development.

Background and aims The influence of pain as well as Quality of Life (QoL) varies in accordance with biological, social, psychological and existential factors. This study investigates the influence of such factors on the relationship between pain and QoL among older adults from a gender perspective. Methods The Swedish National Study on Aging and Care (SNAC-Blekinge) baseline sample comprised 1402 individuals aged 60–96 years, of whom 769 (55%) reported pain. The participants were invited by a letter to take part in the study, which was carried out by research staff in two sessions of three hour each. Participants gave informed consent and completed a questionnaire between the two sessions. The reason for non-participation was registered among subjects who declined the invitation. Pain and insomnia were self-reported. Data on age, gender and if living alone or not were collected from the questionnaire. Co-morbidity was obtained from electronic patients records for a period of up to two years prior to participating in the SNAC study. SoC was measured by a translated short form from the original twenty-nine question instrument. QoL, was estimated using the HRQL Medical Outcome Study-Short Form (SF 12). In a model, pain, age, sex, insomnia, co-morbidity, living alone, sense of coherence (SOC), household economy, education and QoL were calculated through multivariate logistic regression. Results Among women, pain was found to have the highest OR (odds ratio) for low QoL [OR 2.27 (CI 1.36–3.78)], followed by low economic status [OR 1.75 (CI 1.08–2.84)], co-morbidity [OR 1.24 (CI 1.05–1.46)], low SOC [OR 1.08 (CI 1.06–1.10)] and lower age [OR 1.05 (CI 1.02–1.08)]. In men, insomnia was found to be the main contributor to low QoL [OR 1.86 (CI 1.04–3.33)], followed by low SOC [OR 1.08 (CI 1.05–1.11)] and lower age [OR 1.04 (CI 1.01–1.07)]. Conclusions Pain has a strong relationship with low QoL among elderly women. Insomnia is associated with low QoL among men who suffer less from pain. Thus the main result is a striking gender difference: Elderly women suffer from pain, elderly men suffer from insomnia. Implications It is importanttotake accountof sex, age, sleep problems, co-morbidity, SOC and economic status in order to understand the relationship between pain and QoL among older adults.