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Background The transient receptor potential cation channel subfamily V1 (TRPV1) receptor is an important factor in pain transmission. The present Phase 2a study investigated the effect on evoked pain and safety of a topically administered TRPV1-antagonist (ACD440 Gel) in patients with chronic peripheral neuropathic pain (PNP).Methods This was an exploratory, randomized, placebo-controlled double-blind crossover study in patients with probable or definite PNP demonstrating sensory hypersensitivity, assessed as evoked pain on suprathreshold sensory stimulation, i.e. hyperalgesia. The aetiologies included a mix of postherpetic neuralgia, postoperative neuropathic pains, and chemotherapy-induced pain. Patients administered ACD440 Gel twice daily onto the painful area(s) for 7 days. Primary endpoint was hyperalgesia to brush, cold, heat, and pinprick. Secondary endpoints included spontaneous pain and Neuropathic Pain Symptom Inventory Questionnaire (NPSI). Due to a significant period effect, a post hoc analysis was conducted, including only period 1 data, i.e. a parallel group comparison.Results Fourteen patients were enrolled and completed the study. ACD440 Gel reduced pain intensity evoked by a 40 degrees C thermoroller stimulus in heat hyperalgesic patients, by ACD440 from median 6 (IQR 4.75, 7.75) to 1.5 (IQR 0.75, 2.25), i.e. by -5.0 (95%CI -11.2, 1.2) vs placebo from median 4 (IQR 3.5, 5.0) to median 5.0 (IQR 4.5, 6.5), i.e. by 1.3 (95%CI -1.5, 4.2), p = 0.029. There were no adverse events induced by study treatment. Evoked mechanical hyperalgesia and brush allodynia were not significantly affected, p = 0.07.Conclusion ACD440 Gel demonstrated a significant analgesic effect on thermally evoked pain, especially in suprathreshold heat pain. This is congruent with an attenuation of thermal hyperalgesia in chronic neuropathic pain patients with C-fibre mediated pain, while there was no effect on evoked pain related to A beta and A delta stimuli. The results support further clinical development in patients with thermally induced C-fibre mediated pain.

It is not known why some patients develop persistent pain after nerve trauma while others do not. Among multiple risk factors for the development of persistent posttrauma and postsurgical pain, a neuropathic mechanism due to iatrogenic nerve lesion has been proposed as the major cause of these conditions. Because there is some evidence that the human leukocyte antigen (HLA) system plays a role in persistent postsurgical pain, this study aimed to identify the genetic risk factors, specifically among HLA loci, associated with chronic neuropathic pain after traumatic nerve injuries and surgery in the upper extremities. Blood samples were taken to investigate the contribution of HLA alleles (ie, HLA-A, HLA-B, HLA-DRB1, HLA-DQB1, and HLA-DPB1) in a group of patients with persistent neuropathic pain (n = 70) and a group of patients with neuropathy without pain (n = 61). All subjects had intraoperatively verified nerve damage in the upper extremity. They underwent bedside clinical neurological examination to identify the neuropathic pain component according to the present grading system of neuropathic pain. Statistical analyses on the allele and haplotype were conducted using the BIGDAWG package. We found that the HLA haplotype A*02:01-B*15:01-C*03:04-DRB1*04:01-DQB1*03:02 was associated with an increased risk of developing persistent neuropathic pain in the upper extremity (OR = 9.31 [95% CI 1.28-406.45], P < 0.05). No significant associations were found on an allele level when correcting for multiple testing. Further studies are needed to investigate whether this association is on a haplotypic level or if certain alleles may be causing the association.

OBJECTIVES: Peripheral neuropathies that occur secondary to nerve injuries may be painful or painless, and including a low-grade inflammation and pro-inflammatory cytokines associated with both regeneration and damage of peripheral nerve cells and fibers. Currently, there are no validated methods that can distinguished between neuropathic pain and painless neuropathy. The aim of this study was to search for proinflammatory and anti-inflammatory proteins associated with pain and experimental pain sensitivity in subjects with surgeon-verified nerve injuries in the upper extremities.

METHODS: One hundred and thirty-one subjects [69 with neuropathic pain, NP; 62 with painless neuropathy, nP] underwent a conditioned pain modulation (CPM) test that included a cold pressor task (CPT) conducted with the non-injured hand submerged in cold water (4 °C) until pain was intolerable. CPM was assessed by pain ratings to pressure stimuli before and after applying the CPT. Efficient CPM effect was defined as the ability of the individual's CS to inhibit at least 29% of pain (eCPM). The subjects were assigned to one of two subgroups: pain sensitive (PS) and pain tolerant (PT) after the time they could tolerate their hand in cold water (PS<40 s and PT=60 s) . Plasma samples were analyzed for 92 proteins incorporated in the inflammation panel using multiplex Protein Extension Array Technology (PEA). Differentially expressed proteins were investigated using both univariate and multivariate analysis (principal component analysis-PCA and orthogonal partial least-squares discriminant analysis-OPLS-DA).

RESULTS: Significant differences in all protein levels were found between PS and PT subgroups (CV-ANOVA p<0.001), but not between NP and nP groups (p=0.09) or between inefficient CPM (iCPM) and eCPM (p=0.53) subgroups. Several top proteins associated with NP could be detected using multivariate regression analysis such as stromelysin 2 (MMPs), interleukin-2 receptor subunit beta (IL2RB), chemokine (C-X-C motif) ligand 3 (CXCL3), fibroblast growth factor 5 (FGF5), chemokine (C-C motif) ligand 28 (CCL28), CCL25, CCL11, hepatocyte growth factor (HGF), interleukin 4 (IL4), IL13. After adjusting for multiple testing, none of these proteins correlated significantly with pain. Higher levels of CCL20 (p=0.049) and CUB domain-containing protein (CDCP-1; p=0.047) were found to correlate significantly with cold pain sensitivity. CDCP-1 was highly associated with both PS and iCPM (p=0.042).

CONCLUSIONS: No significant alterations in systemic proteins were found comparing subjects with neuropathic pain and painless neuropathy. An expression of predominant proinflammatory proteins was associated with experimental cold pain sensitivity in both subjects with pain and painless neuropathy. One these proteins, CDC-1 acted as "molecular fingerprint" overlapping both CPM and CPT. This observation might have implications for the study of pain in general and should be addressed in more detail in future experiments.

Background & aims: Intensive nutritional therapy is an essential component of burn care. Regardingpost-minor burn injuries, the literature is lacking. The aim of this study was to evaluate documentednutritional therapy in relation to international guidelines after both minor and major burn injuries. The secondary aim of this study was to evaluate the adequacy of energy and protein intake compared toindividual nutritional goals post-burn injury.

Methods: A retrospective observational single-centre study including patients admitted between 2017and 2019 at a burn centre in Sweden was performed. The patients included in the study were >18 years old and in need of hospital care for > 72 h post-burn injury. Information about patients' demographics,nutritional therapy, and clinical characteristics of burn injury was collected. The patients were dividedaccording to total body surface area burnt (TBSA %) into minor burn injuries (TBSA <20%) and major burninjuries (TBSA >20%). Descriptive statistics were used to analyse data. Adherence to guidelines wasestablished by comparing 24 nutritional therapy recommendations to documented treatment. If documented nutritional treatment were in accordance with guidelines, adherence was considered high(>80%), moderate (60-79.9%) or low (<59.9%).

Results: One hundred thirty-four patients were included, 90 patients with minor burn injuries and 44patients with major burn injuries. Documented adherence to the nutritional guideline was overall low.After minor burn injury, 8% (2/24) of nutritional therapy recommendations had a high adherence (fatintake <35% of total energy intake and enteral nutrition as prioritized feeding route), 17% (4/24) amoderate adherence, and 75% (18/24) a low adherence. In patients treated after a major burn injury,there were two recommendations with documented high adherence (Vitamin C and Zinc); 25% (6/24)had moderate adherence, and 67% (16/24) had low adherence. In addition, quite a large amount ofmissing data was found.Adequacy of documented nutritional intake, compared to the individual documented goal, was 78%(±23%) for energy and 66% (±22%) for protein after minor burn injury. After major burn injury, the adequacy was 89% (±21%) for energy and 78% (±19%) for protein, respectively.

Conclusions: This study revealed low adherence to nutritional guidelines in patients treated for minorand major burn injuries. Compared to major burn injuries, lower documented adequacy for both energyand proteins was found in minor burn injuries. Given the disparity between guidelines and documentednutritional therapy, and the lack of specific guidelines for minor burn injuries, there could be aconsiderable risk of inadequate nutritional therapy post-burn injury.

Valid assessment of pain is essential in daily clinical practice to enhance the quality of care for the patients and to avoid the risk of addiction to strong analgesics. The aim of this paper is to find a method for objective and quantitative evaluation of pain using multiple physiological markers. Data was obtained from healthy volunteers exposed to thermal and ischemic stimuli. Twelve subjects were recruited and their physiological data including skin conductance, heart rate, and skin temperature were collected via a wrist-worn sensor together with their selfreported pain on a visual analogue scale (VAS). Statistically significant differences (p < 0.01) were found between physiological scores obtained with the wearable sensor before and during the thermal test. Test-retest reliability of sensor-based measures was good during the thermal test with intraclass correlation coefficients ranging from 0.22 to 0.89. These results support the idea that a multi-sensor wearable device can objectively measure physiological reactions in the subjects due to experimentally induced pain, which could be used for daily clinical practice and as an endpoint in clinical studies. Nevertheless, the results indicate a need for further investigation of the method in real-life pain settings.

Introduction: Sex-related influences represent a contributor to greater pain sensitivity and have a higher prevalence of many chronic pain conditions, including neuropathic pain (NP), among women.

Objectives: The aim was to analyze how differences in ongoing pain, experimental pain intensity, and conditioned pain modulation (CPM) relate to sex in subjects with neuropathy after traumatic nerve injuries.

Methods: Endogenous pain modulation was compared between male (n = 77) and female (n = 55) subjects and between subjects with NP (female = 31, male = 39) and pain-free subjects with posttraumatic neuropathy (female = 24, male = 38). Conditioned pain modulation was assessed by pain ratings to pressure stimuli before and after a noxious conditioning stimulus (CS) conducted with one arm submerged in cold water (4 degrees C) for 1 minute. Time of recovery (Time off) of pain intensity from peak VAS(maxc) after CS was recorded and compared between male and female patients.

Results: Greater ongoing pain intensity was found among female patients compared with male patients and more experimental pain after pressure and cold induced pain. Summing all groups together, women had 0.8 times higher odds (20%) of recovering sooner than men after CS (95% CI = 0.65-2.9). No differences in CPM, time off, and psychosocial variables were seen between female and male patients (P < 0.05).

Conclusion: Our hypothesis for sex differences in endogenous pain modulation was only supported by a shorter after-sensation time after cold CS in female patients. No sex differences in the magnitude of CPM effect were identified. Increased pain intensity for experimental pain, in both neuropathic pain and neuropathy without pain, was found in female patients.

Disease Related Appetite Questionnaire (DRAQ) and Eating Symptom Questionnaire(ESQ) are used to assess nutrition impact symptoms, which are symptoms that can negatively affectthe patients’ food intake. However, these questionnaires have not yet been adapted to the needsof patients recovering from burn injuries. Our aim was therefore to develop DRAQ and ESQ forassessments of nutrition impact symptoms after burn injury. A content validation index (I-CVI) foritems included in DRAQ and ESQ, regarding their relevance for possible nutrition impact symptomsin a burn-injured patient (Likert scale 1–4), was performed by an expert review group. A clarityvalidation by expert and non-expert reviewers was carried out. Two of the eleven questions inDRAQ and eight of the fourteen questions in ESQ were not considered relevant and were thereforeremoved from the questionnaires. Five additional questions were added to DRAQ and two to ESQ.A high degree of consensus on relevance (scale-content validity index average, S-CVI/Ave, 0.86 forDRAQ-burn and 0.83 for ESQ-burn) was reached in the expert group. To conclude, it is suggestedthat we use developed forms of DRAQ and ESQ (DRAQ-burn and ESQ-burn) for the assessment ofnutrition impact symptoms, specifically during the rehabilitation phase of burn-injured patients.

A 48-year-old man with attention deficit disorder, obesity, sleep apnea and a previous history of addiction to amphetamine was admitted with 4% burn injury in the Emergency Department (ER) after he was found unresponsive in a hot air sauna. On his arrival on ER the patient was drowsy and confused (Reaction Level Scale-RLS 3), but responds to strong stimulation. He was intubated and required intensive care treatment. Opioid toxicity was suspected and the examination revealed a 100 μg/h Fentanyl patch on his right shoulder. The exposure to heat is known to increase the rate and extent of opioid delivery in patients with transdermal fentanyl patches. The unconsciousness caused by fentanyl overdose, the immobility and the prolonged exposure to hot air resulted in full-thickness burns. The heat exposure associated with hot air sauna resulted in an extremely complex injury with full-thickness skin damage and deep tissue destruction. The burn injuries required several surgical interventions with debridement, allogenic skin graft, dermal substitute and local flaps. This case report highlights the risk of overdose associated with fentanyl patches, but also the challenges associated with burn treatment in patients exposed to hot air sauna.

Background: 

As yet, there is limited research that can identify factors that differentiate between painful and nonpainful neuropathies after traumatic nerve injury. The aim of this study was to compare subjects with pain and without pain, all after operative nerve repair in the upper extremities.

Methods: 

Subjects in both groups (pain, n = 69; painless, n = 62) underwent clinical assessment of sensory nerve function and psychophysical tests: quantitative sensory testing and conditioned pain modulation (CPM). Conditioned pain modulation was assessed by pain ratings to 120 seconds pressure stimuli administered before and after a 60 seconds noxious 4°C cold conditioning stimulus (CS). Time of recovery (time off) of pain intensity from peak VAS_maxc after CS was recorded. Questionnaires about the quality of life (RAND-36) and disability of the extremity (QuickDash) were completed.

Results: 

There were no significant differences between groups for CPM (P = 0.19). Time off was 42 seconds in subjects with pain in comparison with 28 seconds in those without pain (P < 0.0001). Compared with individuals reporting no pain, participants with neuropathic pain after nerve injuries had 1.8 times the odds of recovering later after CS, gain of function findings at sensory examination (P < 0.0001), lower scores of the physical component of RAND-36 (P < 0.0001), and increase arm disability (P < 0.0001). Hyperesthesia to cold pain stimulation (P = 0.03) and lowered pain pressure threshold (P = 0.01) were found in the pain group.

Conclusion: 

Recovery after the pain induced by cold CS indicates changes in central processing of pain and provides a potential measurement of endogenous pain modulation in individuals with chronic neuropathic pain.

Background and aims

Aside from the long term side effects of a nerve injury in the upper extremity with devastating consequences there is often the problem of chronic neuropathic pain. The studies concerning the prevalence of persistent pain of neuropathic origin after peripheral nerve injuries are sparse. The prevalence and risk factors associated with chronic neuropathic pain after nerve injuries in the upper extremity were assessed.

Methods

A standardized data collection template was employed prospectively and retrospectively for all patients with traumatic nerve injuries accepted at the Hand Surgery Department, Uppsala, Sweden between 2010 and 2018. The template included demographic data, pain diagnosis, type of injured nerve, level of injury, date of the lesion and repair, type of procedure, reoperation, time since the procedure, S-LANSS questionnaire (Self report-Leeds Assessment of Neuropathic Symptoms and Signs), RAND-36 (Item short form health survey), QuickDASH (Disability of Shoulder, Arm and Hand) and additional questionnaires concerned medication, pain intensity were sent to 1,051 patients with nerve injuries. Partial proportional odds models were used to investigate the association between persistent pain and potential predictors.

Results

More than half of the patients undergoing a surgical procedure developed persistent pain. Prevalence of neuropathic pain was 73% of the patients with pain (S-LANSS ≥ 12 or more). Multivariate analysis indicated that injury of a major nerve OR 1.6 (p = 0.013), years from surgery OR 0.91 (p = 0.01), younger age OR 0.7 (p < 0.001), were the main factors for predicting pain after surgery. The type of the nerve injured was the strongest predictor for chronic pain with major nerves associated with more pain (p = 0.019).

Conclusions

A high prevalence of chronic pain and neuropathic pain with a negative impact on quality of life and disability were found in patients after traumatic nerve injury. Major nerve injury, younger age and less time from surgery were predictors for chronic pain.