What is known and what is still unknown within chronic musculoskeletal pain? A systematic evidence and gap map.

ABSTRACT: Evidence and gap maps (EGMs) can be used to identify gaps within specific research areas and help guide future research agendas and directions. Currently, there are no EGMs within the broad domain of chronic musculoskeletal (MSK) pain in adults. The aim of this study was to create a contemporary EGM of interventions and outcomes used for research investigating chronic MSK pain. This EGM was based on systematic reviews of interventions published in scientific journals within the past 20 years. Embase, PubMed, the Cochrane Library, and PsycINFO were used to retrieve studies for inclusion. The quality of the included reviews was assessed using AMSTAR-II. Interventions were categorised as either physical, psychological, pharmacological, education/advice, interdisciplinary, or others. Outcomes were categorised using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations. Of 4299 systematic reviews, 457 were included. Of these, 50% were rated critically low quality, 25% low quality, 10% moderate quality, and 15% rated high quality. Physical interventions (eg, exercise therapy) and education were the most common interventions reported in 80% and 20% of the studies, respectively. Pain (97%) and physical functioning (87%) were the most reported outcomes in the systematic reviews. Few systematic reviews used interdisciplinary interventions (3%) and economic-related outcomes (2%). This contemporary EGM revealed a low proportion of high-quality evidence within chronic MSK pain. This EGM clearly outlines the lack of high-quality research and the need for increased focus on interventions encompassing the entire biopsychosocial perspective.

Participatory research: a Priority Setting Partnership for chronic musculoskeletal pain in Denmark.

OBJECTIVES: Patient and stakeholder engagements in research have increasingly gained attention in healthcare and healthcare-related research. A common and rigorous approach to establish research priorities based on input from people and stakeholders is the James Lind Alliance Priority Setting Partnership (JLA-PSP). The aim of this study was to establish research priorities for chronic musculoskeletal (MSK) pain by engaging with people living with chronic MSK pain, relatives to people living with chronic MSK pain, healthcare professionals (HCP), and researchers working with chronic MSK pain. METHODS: This JLA-PSP included a nation-wide survey in Denmark, an interim prioritisation, and an online consensus building workshop. The information gained from this was the basis for developing the final list of specific research priorities within chronic MSK pain. RESULTS: In the initial survey, 1010 respondents (91% people living with chronic MSK pain/relatives, 9% HCPs/researchers) submitted 3121 potential questions. These were summarised into 19 main themes and 36 sub-themes. In the interim prioritisation exercise, 51% people living with pain/relatives and 49% HCPs/researchers reduced the list to 33 research questions prior to the final priority setting workshop. 23 participants attended the online workshop (12 people/relatives, 10 HCPs, and 1 researcher) who reached consensus for the most important research priorities after two rounds of discussion of each question. CONCLUSIONS: This study identified several specific research questions generated by people living with chronic MSK pain, relatives, HCPs, and researchers. The stakeholders proposed prioritization of the healthcare system's ability to support patients, focus on developing coherent pathways between sectors and education for both patients and HCP. These research questions can form the basis for future studies, funders, and be used to align research with end-users' priorities.

Significantly higher use of polypharmacy in elderly with hip fracture treated with psychotropics.

INTRODUCTION: The high prevalence of chronic medical conditions among older adults leads to an increased use of prescription medications and a heightened risk of polypharmacy, raising the risk of falls and fractures. Psychotropic medications influence balance, and therefore our aim was to describe the use of psychotropic medications and the association with polypharmacy in elderly patients with a hip fracture. METHODS: A retrospective study of 200 patients aged 65 years or more admitted consecutively with a hip fracture. RESULTS: In total, 98 of the 200 patients used psychotropic medications. These 98 patients used a higher number of drugs at the time of admission (an average of eight (6-11) versus six (3-10), p less-than0.001), had a higher risk of using five or more medications (odds ratio (OR) = 5.9; 95% confidence interval (CI): 2.75-12.7; p less-than 0.001) and a higher risk of using ten or more medications (OR = 1.9; 95% CI: 1.05-3.5; p = 0.03). Furthermore, they were more likely to use analgesics (65.3% versus 48.0%; p = 0.01) and medications targeting the gastrointestinal tract (59.1% versus 40.2%; p = 0.01). CONCLUSIONS: Psychotropic medication use was frequent in elderly patients with a hip fracture and strongly associated with polypharmacy. Psychotropic medications may potentially be a trigger to perform medication review in elderly patients to prevent re-occurrence hip fractures. FUNDING: none. TRIAL REGISTRATION: not relevant.

Effect of Roux-en-Y gastric bypass on the pharmacokinetic-pharmacodynamic relationships of liquid and controlled-release formulations of oxycodone.

The physiological changes following Roux-en-Y gastric bypass (RYGB) surgery may impact drug release from mechanistically different controlled-release tablets, making generic substitution inappropriate. This study aimed to characterise the pharmacokinetic-pharmacodynamic relationships of oxycodone from a lipid-based and water-swellable controlled-release tablet in RYGB patients. Twenty RYGB patients received 10-mg oral solution oxycodone or 20-mg controlled-release (water-swellable or lipid-based) oxycodone in a three-way, randomised, semiblinded and cross-over study. Blood sampling and pupillary recordings were conducted over a 24-h period. A previously established pharmacokinetic-pharmacodynamic model of these three formulations in healthy volunteers was used in the analysis as a reference model. No differences in absorption kinetics were seen between controlled-release formulations in patients. However, the absorption lag time was 11.5 min in patients vs 14 min in healthy volunteers for controlled-release tablets (P < 0.001). Furthermore, oral bioavailability was 14.4% higher in patients compared to healthy volunteers regardless of formulation type (P < 0.001). Oxycodone pharmacodynamics were not significantly affected by formulation or patient status. However, baseline pupil diameter was inversely correlated with age (P < 0.001) and plasma concentrations of oxycodone at half-maximum effect were 31% lower in males compared to females (P < 0.05). Generic substitution of monophasic lipid-based and water-swellable controlled-release oxycodone tablets may be considered safe in RYGB patients.

Gastrointestinal pH, Motility Patterns, and Transit Times After Roux-en-Y Gastric Bypass.

BACKGROUND: Studies investigating the underlying pathophysiology are needed to help explain and understand the postoperative complications following Roux-en-Y gastric bypass (RYGB) surgery. This study aimed to characterize segmental gastrointestinal pH profiles, motility measures, and transit times in patients with RYGB. MATERIALS AND METHODS: Nineteen patients with RYGB underwent a standardized wireless motility capsule assessment. The oro-cecal segment was defined from capsule ingestion until the passage of the ileocecal junction. Segmental median pH, motility index, and transit time were determined for the oro-cecal and colonic segment as well as for the first and last hour of both these segments. For comparison to reference values, data from 17 healthy age- and gender-matched controls was used. A mixed effect model was used to describe differences between groups. RESULTS: Median pH was high in patients with RYGB during the first hour of the oro-cecal segment (6.45 ± 0.4 vs 3.65 ± 1.55 pH units for healthy controls; P < 0.001), as well as during the entire oro-cecal segment (6.97 ± 0.4 vs 5.51 ± 1.1 pH units; P < 0.001). The same was evident for the median motility index (152 ± 64 vs 35.8 ± 31.1 mmHg*sec/min; P < 0.001 and 130 ± 65.9 vs 89.1 ± 20 mmHg*sec/min; P < 0.012, respectively). Median motility index was low the first hour of the colon (55.2 ± 45.7 vs 122 ± 77.9 mmHg*sec/min; P < 0.002). Additionally, patients had short oro-cecal transit time (5.8 ± 1.6 vs 7.6 ± 1.4 h; P < 0.001) and long colonic transit time (29.4 ± 17.5 vs 19.6 ± 12.2 h; P = 0.048). CONCLUSIONS: In patients with RYGB, the oro-cecal segment was characterized by an alkaline intraluminal environment, high motility activity, and short transit time. In contrast, colonic transit time was long.

The association between initial opioid type and long-term opioid use after hip fracture surgery in elderly opioid-naïve patients.

Objectives Long-term opioid use after hip fracture surgery has been demonstrated in previously opioid-naïve elderly patients. It is unknown if the opioid type redeemed after hip surgery is associated with long-term opioid use. The aim of this study was to examine the association between the opioid type redeemed within the first three months after hip fracture surgery and opioid use 3-12 months after the surgery. Methods A nationwide population-based cohort study was conducted using data from Danish health registries (2005-2015). Previously opioid-naïve patients registered in the Danish Multidisciplinary Hip Fracture Registry, aged ≥65 years, who redeemed ≥1 opioid prescription within three months after the surgery, were included. Long-term opioid use was defined as ≥1 redeemed prescription within each of three three-month periods within the year after hip fracture surgery. The proportion with long-term opioid use after surgery, conditioned on nine-month survival, was calculated according to opioid types within three months after surgery. Adjusted odds ratios (aOR) for different opioid types were computed by logistic regression analyses with 95% confidence intervals (CI) using morphine as reference. Subgroup analyses were performed according to age, comorbidity and calendar time before and after 2010. Results The study included 26,790 elderly, opioid-naïve patients with opioid use within three months after hip fracture surgery. Of these patients, 21% died within nine months after the surgery. Among the 21,255 patients alive nine months after surgery, 15% became long-term opioid users. Certain opioid types used within the first three months after surgery were associated with long-term opioid use compared to morphine (9%), including oxycodone (14%, aOR; 1.76, 95% CI 1.52-2.03), fentanyl (29%, aOR; 4.37, 95% CI 3.12-6.12), codeine (13%, aOR; 1.55, 95% CI 1.14-2.09), tramadol (13%, aOR; 1.56, 95% CI 1.35-1.80), buprenorphine (33%, aOR; 5.37, 95% CI 4.14-6.94), and >1 opioid type (27%, aOR; 3.83, 95% CI 3.31-4.44). The proportion of long-term opioid users decreased from 18% before 2010 to 13% after 2010. Conclusions The findings suggest that use of certain opioid types after hip fracture surgery is more associated with long-term opioid use than morphine and the proportion initiating long-term opioid use decreased after 2010. The findings suggest that some elderly, opioid-naïve patients appear to be presented with untreated pain conditions when seen in the hospital for a hip fracture surgery. Decisions regarding the opioid type prescribed after hospitalization for hip fracture surgery may be linked to different indication for pain treatment, emphasizing the likelihood of careful and conscientious opioid prescribing behavior.

Gastrointestinal pain.

Gastrointestinal (GI) pain - a form of visceral pain - is common in some disorders, such as irritable bowel syndrome, Crohn's disease and pancreatitis. However, identifying the cause of GI pain frequently represents a diagnostic challenge as the clinical presentation is often blurred by concomitant autonomic and somatic symptoms. In addition, GI pain can be nociceptive, neuropathic and associated with cancer, but in many cases multiple aetiologies coexist in an individual patient. Mechanisms of GI pain are complex and include both peripheral and central sensitization and the involvement of the autonomic nervous system, which has a role in generating the symptoms that frequently accompany pain. Treatment of GI pain depends on the precise type of pain and the primary disorder in the patient but can include, for example, pharmacological therapy, cognitive behavioural therapies, invasive surgical procedures, endoscopic procedures and lifestyle alterations. Owing to the major differences between organ involvement, disease mechanisms and individual factors, treatment always needs to be personalized and some data suggest that phenotyping and subsequent individual management of GI pain might be options in the future.

Population pharmacokinetic-pharmacodynamic modelling of liquid and controlled-release formulations of oxycodone in healthy volunteers.

Oral controlled-release formulations are playing an ever-increasing role in opioid therapy; however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic-pharmacodynamics of two controlled-release tablet formulations and a liquid formulation of oxycodone in healthy, opioid-naïve volunteers, which can serve as a reference for future patient studies. A semi-double-blinded, three-way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled-release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post-dose. Oxycodone pharmacokinetics was best described by a two-compartment model with first-order absorption. The controlled-release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (kaCR  = 0.19 hour-1 ) compared to the oral solution (kaSOL  = 0.94 hour-1 ). Effects on pupil diameter were delayed relative to plasma (14 minutes half-life) for all formulations and were best described by a proportional Emax model. The plasma concentration of oxycodone at half-maximum effect was lower in males (31.1 µg/L) compared to females (52.8 µg/L; P < .001). The absorption profile of controlled-release oxycodone formulations provided a prolonged onset and offset of action compared to oral solution oxycodone. The controlled-release formulations showed no differences in pharmacokinetic and pharmacodynamic parameters suggesting that both may be used interchangeably in human beings with normal gastrointestinal function.

Chronic abdominal pain and persistent opioid use after bariatric surgery.

Background and aims Bariatric surgery remains a mainstay for treatment of morbid obesity. However, long-term adverse outcomes include chronic abdominal pain and persistent opioid use. The aim of this review was to assess the existing data on prevalence, possible mechanisms, risk factors, and outcomes regarding chronic abdominal pain and persistent opioid use after bariatric surgery. Methods PubMed was screened for relevant literature focusing on chronic abdominal pain, persistent opioid use and pharmacokinetic alterations of opioids after bariatric surgery. Relevant papers were cross-referenced to identify publications possibly not located during the ordinary screening. Results Evidence regarding general chronic pain status after bariatric surgery is sparse. However, our literature review revealed that abdominal pain was the most prevalent complication to bariatric surgery, presented in 3-61% of subjects with health care contacts or readmissions 1-5 years after surgery. This could be explained by behavioral, anatomical, and/or functional disorders. Persistent opioid use and doses increased after bariatric surgery, and 4-14% initiated a persistent opioid use 1-7 years after the surgery. Persistent opioid use was associated with severe pain symptoms and was most prevalent among subjects with a lower socioeconomic status. Alteration of absorption and distribution after bariatric surgery may impact opioid effects and increase the risk of adverse events and development of addiction. Changes in absorption have been briefly investigated, but the identified alterations could not be separated from alterations caused solely by excessive weight loss, and medication formulation could influence the findings. Subjects with persistent opioid use after bariatric surgery achieved lower weight loss and less metabolic benefits from the surgery. Thus, remission from comorbidities and cost effectiveness following bariatric surgery may be limited in these subjects. Conclusions Pain, especially chronic abdominal, and persistent opioid use were found to be prevalent after bariatric surgery. Physiological, anatomical, and pharmacokinetic changes are likely to play a role. However, the risk factors for occurrence of chronic abdominal pain and persistent opioid use have only been scarcely examined as have the possible impact of pain and persistent opioid use on clinical outcomes, and health-care costs. This makes it difficult to design targeted preventive interventions, which can identify subjects at risk and prevent persistent opioid use after bariatric surgery. Future studies could imply pharmacokinetic-, pharmacodynamics-, and physiological-based modelling of pain treatment. More attention to social, physiologic, and psychological factors may be warranted in order to identify specific risk profiles of subjects considered for bariatric surgery in order to tailor and optimize current treatment recommendations for this population.

Correction: Predictors of opioid efficacy in patients with chronic pain: A prospective multicenter observational cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0171723.].

Effects of Naloxegol on Gastrointestinal Transit and Colonic Fecal Volume in Healthy Participants Receiving Oxycodone.

BACKGROUND/AIMS: Opioids cause gastrointestinal (GI) dysmotility, decrease gut secretion, and affect gut sphincters. Symptoms of opioid-induced bowel dysfunction may be alleviated by peripherally acting opioid antagonists like naloxegol, but detailed knowledge on GI effects of this drug is lacking. We hypothesized that naloxegol, compared to placebo, would reduce GI transit time and colonic fecal volume in opioid-treated healthy participants. METHODS: We conducted a randomized, double-blinded, single-center, 2-way cross-over study in 24 healthy males, randomized to a 6 day treatment period of oxycodone (15 mg twice a day) co-administered with either naloxegol (25 mg once a day) or matching placebo. Participants swallowed an electromagnetic capsule which determined GI transit times. Colonic fecal volume was quantified with magnetic resonance imaging both pre-treatment and post-treatment. RESULTS: Naloxegol reduced total GI transit time by 21% (56 hours vs 71 hours, P = 0.02) and colonic transit time by 23% (45 hours vs 59 hours, P < 0.01), compared to placebo. However, no difference in colonic fecal volume was found (818 mL vs 884 mL, P = 0.20). CONCLUSION: Short-term administration of naloxegol in healthy participants reverses the retardation of total GI and colonic transit induced by oxycodone. This supports the use of naloxegol in the treatment of GI side effects to opioid treatment, and add knowledge to the current understanding of mechanisms behind peripherally-acting opioid antagonists.

Patient and Disease Characteristics Associate With Sensory Testing Results in Chronic Pancreatitis.

BACKGROUND: Abdominal pain is the most common symptom in chronic pancreatitis (CP) and has an extensive impact on patients' lives. Quantitative sensory testing (QST) provides information on sensitivity to pain and mechanisms that can help quantify pain and guide treatment. The aims of this study were (1) to explore sensitivity to pain in patients with CP using QST and (2) to associate patient and disease characteristics with QST results. METHODS: Ninety-one patients with painful CP and 28 healthy control participants completed a QST paradigm using static tests (muscle pressure stimulation and electrical skin stimulations) to unravel segmental and widespread hyperalgesia as a consequence of visceral pain. A dynamic conditioned pain modulation (CPM) paradigm was used as a proxy of pain modulation from the brainstem to inhibit incoming nociceptive barrage, and questionnaires were used to gather information on pain experience and quality of life. RESULTS: Patients had impaired CPM compared with controls (18.0±29.3% vs. 30.9±29.3%, P=0.04) and were hypersensitive to pressure stimulation, specifically in the pancreatic (Th10) dermatome (P<0.001). The capacity of CPM was associated with clinical pain intensity (P=0.01) and (in the univariate analysis only) the use of opioids was associated with hyperalgesia to pressure stimulation (P<0.05). CONCLUSIONS: Sensitivity to pain in CP patients can be characterized by a simple bedside QST. Severe clinical pain in CP was associated with reduced CPM function and should be targeted in management.

Opioid use after hip fracture surgery: A Danish nationwide cohort study from 2005 to 2015.

BACKGROUND: There is currently a knowledge gap regarding persistent opioid use after hip fracture surgery. Thus, opioid use within a year after hip fracture surgery in patients with/without opioid use before surgery was examined. METHODS: This population-based cohort study included all patients (aged ≥ 65) undergoing primary hip fracture surgery in Denmark (2005-2015) identified from the Danish Multidisciplinary Hip Fracture Database. Opioid use was assessed from The Danish National Health Service Prescription Database as redeemed prescriptions. The proportion of patients with ≥1 opioid prescription was computed within 6 months before surgery and each of four 3-month periods (quarters) after surgery, among patients alive first day in each period. Proportion differences (95% CI) were calculated for each quarter compared to before surgery. Proportions were calculated for users and nonusers before surgery, including initiators after first quarter. RESULTS: This study included 69,456 patients. Proportion differences of opioid users were 35.0 (95% CI 34.5-35.5), 7.0 (95% CI 6.5-7.5), 2.9 (95% CI 2.4-3.4) and 1.4 percentage-points (95% CI 0.9-1.9) the four quarters after surgery compared to before. Among opioid nonusers before surgery, 54.7% (95% CI 54.3-55.1), 21.8% (95% CI 21.4-22.2), 17.8% (95% CI 17.4-18.2) and 16.8% (95% CI 16.4-17.2) were opioid users in 1st-4th quarter after surgery. However, 8.5% (95% CI 8.2-8.7) of the nonusers before surgery in 4th quarter initiated opioid use more than a quarter after surgery. CONCLUSIONS: The proportion of opioid users increased after hip fracture surgery and was 1.4 percentage-points increased in fourth quarter compared to before. Of opioid nonusers before surgery, 16.8% were opioid users fourth quarter after surgery. SIGNIFICANCE: Opioid use 1 year after hip fracture surgery is common, both in patients who were opioid users and nonusers before the surgery. These significant findings point out the need for indication of benefits and risks of opioid use in the acute and long-term management of patients undergoing hip fracture surgery.

Mechanism-based pain management in chronic pancreatitis - is it time for a paradigm shift?

INTRODUCTION: Pain is the most common symptom in chronic pancreatitis and treatment remains a challenge. Management of visceral pain, in general, is only sparsely documented, and treatment in the clinic is typically based on empirical knowledge from somatic pain conditions. This may be problematic, as many aspects of the neurobiology differ significantly from somatic pain, and organs such as the gut and liver play a major role in tolerability to analgesics. On the other hand, clinical awareness and new methods for quantitative assessment of pain mechanisms, will likely increase our understanding of the visceral pain system and guide more individualized pain management. Areas covered: This review includes an overview of known pain mechanisms in chronic pancreatitis and how to characterize them using quantitative sensory testing. The aim is to provide a mechanism-oriented approach to analgesic treatment, including treatment of psychological factors affecting pain perception and consideration of side effects in the management plan. Expert opinion: A mechanism-based examination and profiling of pain in chronic pancreatitis will enable investigators to provide a well-substantiated approach to effective management. This mechanism-based, individualized regime will pave the road to better pain relief and spare the patient from unnecessary trial-and-error approaches and unwanted side effects.

A Pragmatic Utility Function to Describe the Risk-Benefit Composite of Opioid and Nonopioid Analgesic Medication.

It is not straightforward to simultaneously evaluate the beneficial and harmful effects of pain management, since different drugs may possess different analgesia and adverse effect profiles. Utility functions, derived from the pharmacokinetics and pharmacodynamics of individual outcome parameters, have been constructed to address this problem. Here, we construct "pragmatic" utility functions based on measurements of benefit and harm, but without making assumptions about the underlying pharmacokinetics and pharmacodynamics. Using data from two previous studies, utility functions were designed by estimating the probability of occurrence of benefit and harm and combining these into one function. Study 1 was a clinical trial on the effect of oral pregabalin on pain relief in chronic pancreatitis patients, with endpoint analgesia and dizziness monitored for 21 days. Study 2 was an experimental study on the effect of intravenous fentanyl on antinociception and respiratory depression in healthy volunteers. From study 1, the utility function was negative the first week of treatment, indicative of the greater probability of dizziness than analgesia, but positive thereafter. From study 2, the utility function showed a nadir 30 minutes after dosing, after which the probability function slowly increased toward zero. A pragmatic utility function based on the probability of two binary outcomes, analgesia and adverse effect, was successfully constructed using data from the two previous studies. The results yielded valuable insights into the utility of treatment and may be highly educative for physicians and potentially used in development of potent analgesics without serious side effects.

Offset Analgesia and The Impact of Treatment with Oxycodone and Venlafaxine: A Placebo-Controlled, Randomized Trial in Healthy Volunteers.

Offset analgesia (OA) is a pain-modulating mechanism described as a disproportionately large decrease in pain intensity evoked by a discrete decrease in stimulus temperature. The role of the opioidergic, serotonergic and noradrenergic systems on OA remains unclear. The aim of this study was to evaluate whether OA is modulated by an opioid (oxycodone) and a serotonin and noradrenaline reuptake inhibitor (venlafaxine) in terms of psychophysical assessments. In this randomized, double-blinded, placebo-controlled cross-over study, 20 healthy male participants (mean age: 24.6 ± 2.5 years) received 10 mg oxycodone, 37.5 mg venlafaxine or placebo twice daily for 5 days in three periods. OA was induced by noxious thermal stimulation on the forearm at baseline and last day of treatment. A control session of constant stimulus intensity was included for comparison. OA magnitude was unaffected by oxycodone and venlafaxine (p = 0.20 and p = 0.90, respectively). Oxycodone affected the control paradigm where a decreased rating of pain intensity was observed compared to placebo (p = 0.001). OA could not be modulated by oxycodone or venlafaxine and may be a robust phenomenon in healthy volunteers and not suitable for exploring pharmacological mechanisms of analgesia in human beings.

The Effect of a Combination of Diclofenac and Methadone Applied as Gel in a Human Experimental Pain Model - A Randomized, Placebo-controlled Trial.

Pain involves responses in which both peripheral and central mechanisms contribute to the generation of pain. Pre-clinical laboratory data have supported that a topical formulation of combined diclofenac and methadone (Diclometh) may alleviate local pain, and potentially, the side effect profile should be low. We hypothesized that antiallodynic and antihyperalgesic effects of Diclometh could be demonstrated in a human experimental pain model and that Diclometh would be safe to administer. Thus, the aims were as follows: (i) to compare two doses of Diclometh versus placebo; and (ii) to assess the safety profile of Diclometh. The study was a crossover, randomized, double-blind, placebo-controlled comparison of two doses of Diclometh gel (0.1% and 0.2%) administered topically in healthy participants. Nerve growth factor (NGF) and capsaicin intradermal injections were used as human pain models. Pressure stimulation, contact heat stimulation, hyperalgesia (pinprick stimulation) and allodynia (brush stimulation) to mechanical stimulation were performed in the area where capsaicin and NGF were injected. Side effects were recorded on a four-point Likert scale. Twenty-one men completed the study (mean age 26.14 ± 5.3). Diclometh 0.2% reduced the capsaicin-induced dynamic mechanical allodynia compared to placebo (primary end-point, p = 0.03). No other primary or secondary end-points were found significantly different (all p > 0.05). All side effects were reported as mild with no differences between treatments (p = 0.15). Indication of antiallodynic effect of Diclometh 0.2% was found. Additionally, it was demonstrated that Diclometh was safe to use.

Differential effects of oxycodone and venlafaxine on resting state functional connectivity-A randomized placebo-controlled magnetic resonance imaging study.

AIM: Different mechanisms may be involved in the antinociceptive effects of oxycodone (opioid) and venlafaxine (serotonin-norepinephrine reuptake inhibitor), and the aim of this study was to investigate the effect of these drugs on brain functional connectivity. METHODS: Resting state functional magnetic resonance imaging was acquired in 20 healthy volunteers before and after a 5-day treatment with oxycodone, venlafaxine, or placebo in a randomized, double-blind, crossover study. Functional connectivity analyses were performed between four predefined seeds (dorsal anterior cingulate cortex, rostral anterior cingulate cortex, posterior insula, and prefrontal cortex), and the whole brain. RESULTS: The overall interpretation was that there were differences between the effects of oxycodone and venlafaxine on functional connectivity. Oxycodone mainly showed decreased functional connectivity between limbic structures and to supralimbic areas (all P < 0.05). Venlafaxine also showed decreased functional connectivity between limbic structures and to supralimbic areas, but increased functional connectivity to structures in the midbrain and brain stem was also found (all P < 0.05). CONCLUSIONS: Oxycodone and venlafaxine showed differential effects on resting-state functional connectivity as compared to placebo. This supports that the two drugs exert different mechanisms, and that the drugs in combination may exert additive effects and could potentially improve pain therapy.

The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction.

BACKGROUND AND AIMS: Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co-administration of the peripherally acting µ-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo. METHODS: In a double-blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale. RESULTS: During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (-45.9 vs -38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01). CONCLUSIONS: In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process.

Association Between Genetic Polymorphisms and Pain Sensitivity in Patients with Hip Osteoarthritis.

BACKGROUND: Factors such as age, gender, and genetic polymorphisms may explain individual differences in pain phenotype. Genetic associations with pain sensitivity have previously been investigated in osteoarthritis patients, with a focus on the P2X7, TRPV1, and TACR1 genes. However, other genes may play a role as well. Osteoarthritis is a common joint disease, and many patients suffering from this disease are thought to have increased sensitivity to noxious stimuli resulting from sensitization in the nociceptive system. The aim of this study was to investigate if genetic variants of mu, kappa, and delta opioid receptor genes (OPRM1, OPRK1, and OPRD1) and the catechol-O-methyltransferase gene (COMT) influenced the pain phenotype in patients with osteoarthritis. METHODS: The frequencies of 17 polymorphisms were examined. Pain sensitivity was assessed preoperatively by (1) hip rotation, (2) contact heat stimulation, (3) conditioned pain modulation effect, and (4) pressure stimulation at the tibia in both the affected and the unaffected leg. RESULTS: Ninety-two patients (mean age 66 years) with unilateral hip osteoarthritis were included in the study. Carriage of the OPRM1 rs589046T allele was found to be associated with increased pain ratings during hip rotation (P = 0.04) and increased conditioned pain modulation (P = 0.049). Carriage of the OPRD1 rs2234918C allele was found to be associated with an increased pain detection threshold to contact heat stimulation (P = 0.001). No other associations were found (all P > 0.05). CONCLUSION: Results from the present study suggest that, in patients with hip osteoarthritis, genetic variants in OPRM1 and OPRD1 may contribute to the pain phenotype.