The Danish-American Research Exchange (DARE): a cross-sectional study of a binational research education program.

BACKGROUND: Most medical educational programs emphasize clinical observation or clinical skill acquisition, fewer focus upon research. The Danish-American Research Exchange (DARE) program, sponsored by the Lundbeck Foundation, is unique in that the medical student initiates biomedical research collaboration between Danish and US medical institutions. To achieve this, Danish medical students (DARE students) conduct binational mentored research projects while based in the United States for 10 months. In addition, DARE students are introduced to interdisciplinary thinking about how to develop ultra-low-cost healthcare interventions through the '$10 Challenge'. METHODS: We conducted a cross-sectional study of DARE alumni over five consecutive years (2015-2020, n = 24). Research metrics included completion of a research project, primary authorship, and co-authorship of publications. The number of publications, prior to and after the DARE program were enumerated. For the first four cohorts, graduation from medical school and acceptance or intention to enter a joint MD-PhD program also were assessed. Two focus groups were conducted using constructivist grounded theory. Discussions were transcribed, redacted, and coded using Dedoose software. RESULTS: DARE Medical students were 31.2 years (range 24-35), the majority were women (67%;16/24). The majority (17/24;71%) completed a first author publication in a peer-reviewed journal with a median of 3.9 per DARE alumnus. DARE alumnus reported increased proficiency in biostatistics, epidemiology, coding and public speaking as well as stronger research qualities in creativity, critical thinking, comfort in approaching scientist in both the US and Denmark (p < 0.001 for all). Qualitative key themes included: increased confidence, a deepening of research inquiry and linkage to a research network. CONCLUSIONS: Preliminarily, this study suggests that medical students can initiate binational collaboration in medicine. Benefits include research productivity, intention to pursue academic medical careers, as well as positive impacts on motivation. This medical student-initiated research model lays the groundwork for using this model across other country pairs to promote binational collaboration.

Natural history of pain associated with melanoma surgery.

INTRODUCTION: After excision of a primary malignant melanoma (MM), treatment of stage IB or higher MM consists of sentinel lymph node biopsy (SLNB). If malignant cells are identified, a complete lymph node dissection (CLND) can be performed. OBJECTIVE: To determine the natural history of pain and sensory changes after MM surgery. METHODS: We prospectively followed 39 patients (29 SLNB-only, 2 CLND-only, and 8 CLND preceded by SLNB) from before inguinal or axillary surgery through 6 months after surgery on measures of pain intensity, sensory symptoms, allodynia, and questionnaires of anxiety, depression, and catastrophizing. RESULTS: No patient had pain preoperatively. Ten days after surgery, 35% had surgical site pain after SLNB-only compared with 90% after CLND (P < 0.003); clinically meaningful pain (Visual Analogue Scale ≥ 30 mm/100 mm) was reported by 3% of patients after SLNB-only compared with 40% after CLND (P < 0.001). At 6 months, all SLNB-only patients were pain-free. By contrast, 4 of 7 in the SLNB + CLND group still had pain (P < 0.002). At 6 months, symptoms of altered sensation or numbness were reported by 32% and 42% of SLNB-only patients, and by 67% and 67% of patients undergoing CLND surgery (both P > 0.05). CONCLUSION: Acute pain is more common after CLND surgery. Undergoing SLNB followed by more invasive CLND surgery may increase the likelihood of pain at 6 months. Persistent sensory symptoms typical of those associated with nerve injury are more common after CLND. Surgery for MM is a good model for studying the natural history of postsurgical pain and sensory changes.

Placebo-controlled comparison of a morphine/dextromethorphan combination with morphine on experimental pain and hyperalgesia in healthy volunteers.

UNLABELLED: In this double-blind, placebo-controlled, crossover study we compared the analgesic effect of a single oral dose of 30-mg dextromethorphan and 30-mg morphine combination (MS/DM) to 30 mg morphine (MS) alone and either placebo or 30 mg dextromethorphan (DM) on cutaneous sensitization induced by heat/capsaicin (topical) sensitization on the forearm and the brief thermal sensitization model on the thigh in 22 healthy volunteers. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation in both sensitization models and the painfulness of acute thermal noxious stimulation on the upper arm. Compared with placebo, both MS/DM and morphine had some effect on the secondary hyperalgesia and reduced the painfulness of a noxious thermal stimulus. The analgesic effect of MS/DM was not superior to that of morphine on any outcome measure. These results differ from preclinical studies with animal experimental pain models in which DM markedly potentiated the analgesic effects of opioids, but they are in accordance with recent clinical trials for chronic pain. PERSPECTIVE: Adding dextromethorphan to morphine (1:1 ratio) did not enhance analgesia on measures of experimental cutaneous sensitization and acute noxious thermal stimulation in healthy volunteers. The results differ from preclinical studies but agree with clinical trials. Human experimental models of pain and neuronal sensitization, which are responsive to oral opioids, allow efficient study of opioid combination analgesics and simplify the process for determining the optimal dose and/or dose ratio.

Gender differences in pain and secondary hyperalgesia after heat/capsaicin sensitization in healthy volunteers.

UNLABELLED: In most published studies women are more sensitive to experimental pain than men. Enhanced central pain processing in women has been suggested, but psychosocial factors might also have affected the findings. Data from five completed healthy volunteer studies were analyzed to investigate gender differences in development of secondary hyperalgesia. Cutaneous hyperalgesia was induced with the heat/capsaicin sensitization model. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation after heat and capsaicin sensitization, rating of pain during heat/capsaicin sensitization, and heat pain detection thresholds. There was a trend toward smaller areas of secondary hyperalgesia in women. After adjusting for estimated gender differences in forearm surface area, areas to brush but not von Frey hair stimulation after capsaicin sensitization were larger in women. Peak pain, but not total pain, during prolonged noxious thermal stimulation was higher in women. There was no gender difference in pain ratings during capsaicin sensitization or in heat pain detection thresholds. The results provided only limited support to the hypothesis that gender differences in clinical pain syndromes can be explained by enhanced central sensitization in women. PERSPECTIVE: Our findings suggest that gender differences in nociceptive transmission and neuronal sensitization are small and provide only limited support to the hypothesis that gender differences in acute and chronic pain syndromes can be explained by enhanced central sensitization in women.

Complex regional pain syndrome-like symptoms during herpes zoster.

Complex Regional Pain Syndrome (CRPS) associated with herpes zoster (HZ) was first reported by Sudeck in 1901 (Sudeck, 1901) and is recognized clinically. However, only 13 cases have been published in the literature, and nothing is known about the incidence, prevalence, or natural history (Chester, 1992; Foster et al., 1989; Grosslight et al., 1986; Ketz and Schliack,1968; Kishimoto et al., 1995; Querol and Cisneros, 2001; Sudeck, 1901; Visitsunthorn and Prete, 1981). The aim of the present study was to determine the prevalence of CRPS-like symptoms in a prospectively gathered cohort of subjects with HZ and to follow the natural history of their pain and sensory disturbance during the first 6 months after onset of HZ. Subjects were evaluated at four time points after HZ: 2-6 weeks, 6-8 weeks, 3 months, and 6 months. Only subjects aged 50 or older with pain VAS ratings of >/=20/100 at 2-6 weeks were eligible. The first (screening) visit included a neurological and physical examination that was updated at each subsequent visit. Assessments included ratings of pain intensity, allodynia severity, and rash severity. The neurological exam included determination of presence or absence of the following CRPS-like symptoms: (1) increased sweating, (2) color changes, (3) skin temperature changes, (4) weakness of the affected area based on physical exam, (5) edema, and (6) extension of CRPS-like symptoms outside the affected dermatome. For subjects with HZ in dermatomes that can include the limbs (C4-T2 and L1-S2), extremity involvement was considered present if allodynia or rash extended beyond the neck of the humerus (upper extremity), the inguinal ligament (anterior lower extremity), or gluteal sulcus (posterior lower extremity). Involvement of the extremity was considered proximal if neither HZ rash nor allodynia extended past the elbow (upper extremity) or knee (lower extremity). Of the first 75 subjects recruited, 25 had HZ outbreaks in dermatomes that extended into the extremities (C4-T2 and L1-S2). In this group, 8 subjects had no extremity involvement, 8 had proximal extremity involvement, and 9 had distal extremity involvement. Subjects with distal extremity HZ reported more pain across the four visits (p < 0.05). At 3 months, more subjects with distal extremity involvement met criteria for PHN (8 out of 9, 89%), while only 4 out of 8 (50%) with proximal involvement and 2 out of 8 (25%) of subjects without extremity involvement met criteria for PHN (Chi-square test: p < 0.05). Only 25 out of the remaining 50 (50%) subjects with outbreaks in dermatomes that do not include the extremities met criteria for PHN at 3 months (Chi-square test: p < 0.05). Six months after onset of HZ, 6 out of 9 subjects with distal extremity involvement met PHN criteria compared with 2 out of 8 (25%) with proximal involvement and 2 out of 8 (25%) without extremity involvement (Chi-square test: p = 0.12). Fifteen out of 50 (30%) subjects with outbreaks in dermatomes that do not include the extremities met criteria for PHN (Chi-square test: p < 0.05). No subject had all six CRPS-like symptoms. Of the 17 subjects with extremity involvement, 9 subjects had '0-2 CRPS-like symptoms' and 8 had '3-5 CRPS-like symptoms'. None of the eight subjects without extremity involvement had any CRPS-like symptoms. Of the 50 subjects with HZ outside the extremity, only one had abdominal weakness. Pain ratings were higher in subjects with '3-5 CRPS-like symptoms'. More subjects with '3-5 CRPS-like symptoms' met criteria for PHN at 3 months (7 out of 8, 88%), compared to 5 out of 9 (55%) of subjects with '0-2 CRPS-like symptoms' (p = 0.07). At 6 months, 2 out of 9 (22%) of subjects with '0-2 CRPS-like symptoms' met criteria for PHN, compared with 6 out of 8 (75%) of subjects with '3-5 CRPS-like symptoms' (Chi-square test: p < 0.03). Two case-reports are presented. In summary, the occurrence of CRPS-like symptoms is common in subjects with HZ outbreaks affecting the extremity, particularly if the distal extremity is involved. It is uncertain if the pathophysiology underlying the CRPS-like symptoms observed in this study is similar to that of CRPS from other causes, or if it is relatively specific to HZ. Development of PHN is common in subjects who have experienced CRPS-like symptoms. More aggressive preventive treatments may be justified in this high-risk subset of HZ subjects to prevent development of PHN. Prospective randomized controlled studies are needed to determine which subjects are most likely to benefit and when treatment should begin.

Impact of co-morbidity on the risk of first-time myocardial infarction, stroke, or death after single-photon emission computed tomography myocardial perfusion imaging.

The impact of co-morbidity on the cardiovascular risk after single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) remains unclear. We examined the association between a normal versus abnormal SPECT MPI scan on 10-year risk of myocardial infarction, stroke, and all-cause death, overall and according to co-morbidity level. We identified all patients without previous myocardial infarction or cerebrovascular disease, who had an SPECT MPI performed at Aarhus University Hospital Skejby during 1999 to 2011. We categorized the SPECT MPI scan as normal (no defects) or abnormal (reversible and/or fixed defects). Using nationwide medical registries, we obtained information on co-morbidity level (using Charlson co-morbidity index) and outcomes. We used Cox regression to compute hazard ratios with 95% confidence intervals (CIs), adjusting for gender, age, and co-morbidity level. Among 7,040 patients, 4,962 (70%) had normal scans and 2,078 (30%) abnormal scans. Patients with a normal versus abnormal scan had a 10-year risk of 5.7% versus 10.9% for myocardial infarction, 6.0% versus 7.8% for stroke, and 16.5% versus 29.0% for all-cause death. After adjustment, an abnormal scan was associated with increased risk of myocardial infarction (adjusted hazard ratio 1.73, 95% CI 1.37 to 2.18) and all-cause death (1.42, 95% CI 1.23 to 1.65) but not stroke (1.12, 95% CI 0.86 to 1.45). Co-morbidity level did not affect substantially the association between the scan result and the outcomes. In conclusion, independently of co-morbidity level, an abnormal SPECT MPI scan was associated with an increased 10-year risk of myocardial infarction and all-cause death but not stroke.

Effect of a single dose of pregabalin on herpes zoster pain.

BACKGROUND: The effect of pregabalin on acute herpes zoster pain has not been previously evaluated. METHODS: In a randomized, double-blind, placebo-controlled, two-session crossover study the effect of a single oral dose of pregabalin (150 mg) on pain and allodynia was evaluated in 8 subjects with herpes zoster. RESULTS: Over 6 hours of observation, pain decreased by a mean of 33% with pregabalin and 14% with placebo (p < 0.10). Effects on allodynia and SF-MPQ were not significant. CONCLUSIONS: Compared to an earlier study of gabapentin 900 mg for acute zoster pain and allodynia that followed a nearly identical protocol, pregabalin had a similar effect on pain and was well tolerated, with no difference from placebo on sleepiness. Common side effects of light-headedness, unsteady gait, and slowed thinking were almost identical to that observed in the earlier study of gabapentin. Subject recruitment proved difficult in part due to the widespread off-label use of gabapentin and pregabalin for acute zoster pain in our region of the USA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00352651.

Natural history of cutaneous innervation following herpes zoster.

As part of a comprehensive study of the natural history of herpes zoster (HZ), 57 of 94 subjects in a cohort at elevated risk for post-herpetic neuralgia (PHN) consented to collection of 3-mm skin punch biopsies from affected, mirror-image, and distant control skin at baseline and followup visits. As cutaneous innervation is reduced in longstanding severe PHN, we tested the hypothesis that development of PHN is correlated with severity of initial neural injury and/or a failure of neural recovery. Quantitative analysis using single-label PGP9.5 immunofluorescence microscopy showed epidermal profiles were reduced in zoster skin by approximately 40% at study entry compared to control and mirror skin. The density of the subepidermal plexus was approximately 15% lower in zoster skin. Mirror skin was not denervated compared to control skin. Although not significant at all visits, correlations between epidermal nerve fiber density in HZ skin and thermal sensation, allodynia, capsaicin response, and average daily pain all associated more severe abnormalities with lower epidermal innervation. There was limited evidence that the initial neural injury was more severe in the 15 eventual PHN subjects. Overall, pain and pain-related disability resolved the fastest. Sensory abnormalities and symptom aggravation by focal capsaicin application showed partial and selective recovery over 6months. In contrast, cutaneous innervation showed no recovery at all by 6months, conclusive evidence that resolution of pain and allodynia does not require cutaneous reinnervation. A much longer period of observation is needed to determine if zoster-affected skin is ever reinnervated.

Changes in morphine analgesia and side effects during daily subcutaneous administration in healthy volunteers.

Tolerance to the anti-nociceptive effects of opioids develops rapidly in animals. In contrast, humans with chronic pain show little or no loss of pain relief in prospective opioid trials of 4-8 weeks duration. Employing the Brief Thermal Sensitization model to induce transient cutaneous secondary hyperalgesia, we tested the hypothesis that opioid analgesic tolerance would develop rapidly. In this outpatient randomized placebo-controlled study, subjects in the MMMMP group received two injections of subcutaneous morphine 6 mg (150 min apart) on Monday-Thursday (total 48 mg over 4 days) and matching saline placebo on Friday. Subjects in the PPPPM group received placebo on Monday-Thursday and morphine (total 12 mg) on Friday. Sixty-one healthy volunteers were enrolled; morphine side effects accounted for all nine non-completions. Compared to the first placebo day, the reduction in the area of secondary hyperalgesia on the first morphine day was significant and robust in both groups. Morphine suppression of the painfulness of skin heating and elevation of the heat pain detection threshold were also significant. During 4 days of twice-daily injections, the decline in anti-hyperalgesic effects of morphine did not reach statistical significance (p=0.06) compared to placebo. Morphine side effects did not correlate with anti-hyperalgesic effects and withdrawal symptoms did not emerge. As 4 days is the threshold for demonstrating analgesic tolerance to twice-daily morphine in animal models, a longer period of opioid exposure in healthy volunteers might be needed to detect analgesic tolerance.

Relief of post-herpetic neuralgia by surgical removal of painful skin: 5 years later.

Surgical removal of painful skin was first attempted as a treatment for chronic intractable post-herpetic neuralgia (PHN) more than a century ago, but long-term follow-up has rarely been reported. A patient who underwent surgical excision of 294cm(2) of thoracic skin comprising the entire area of pain and allodynia in October 2000 has been followed for 5.5years post-surgery. Our initial report presented evidence of benefit in the form of reduced pain, elimination of allodynia, and reduced medication consumption during the first post-operative year. Unfortunately, pain steadily increased and now exceeds pre-surgery levels despite increased medication use. Pain topography and characteristics are different from pre-surgery and may relate to the pathophysiology of PHN. Skin resection cannot be recommended as a treatment for PHN.

Natural history of pain following herpes zoster.

In a longitudinal observational study of 94 patients (39 M:55 F, mean age 69) at elevated risk for developing post herpetic neuralgia (PHN), the natural history of pain during the first 6 months after herpes zoster (HZ) rash onset was determined. Pain severity and impact were rated using pain-VAS, SF-MPQ, and MPI. Applying a definition of PHN of average daily pain >0/100 on the pain VAS during the last 48 h, 30 subjects had PHN at 6 months. These 30 subjects reported more pain and a higher SF-MPQ score (p<0.01) at study inclusion than the 64 subjects whose pain completely resolved by 6 months. At 6 months, mean daily pain in the PHN group was 11/100 (95% CI 5,16) and only nine of these subjects were still taking prescription medication for HZ pain. The rate of recovery (pain severity over time) was the same in the PHN and no-pain groups. At study inclusion, the SF-MPQ and MPI scores in our PHN group were similar to historical controls with chronic severe PHN enrolled in clinical trials, but by 6 months the scores in our PHN subjects were significantly lower than historic controls. Only two subjects met the more stringent criteria for 'clinically meaningful' PHN at 6 months (> or = 30/100 on the pain VAS). Defining PHN as average daily pain >0/100 at 6 months after rash onset appears to substantially overestimate the number of HZ patients negatively impacted by ongoing pain and disability.

A single dose of gabapentin reduces acute pain and allodynia in patients with herpes zoster.

This randomized, double-blind, placebo-controlled crossover study measured the effect of a single dose of oral gabapentin (900 mg) on pain and allodynia associated with herpes zoster. Pain severity decreased by 66% with gabapentin compared to 33% with placebo. Reductions in allodynia area and severity, and overall pain relief, were also greater with gabapentin.