Topically applied novel TRPV1 receptor antagonist, ACD440 Gel, reduces evoked pain in healthy volunteers, a randomized, double-blind, placebo-controlled, crossover study.

BACKGROUND: The TRPV1 receptor is a key molecule in pain generation. Previous development of oral TRPV1-antagonists was halted due to systemic heat insensitivity and body temperature alterations. The present Phase 1b study investigated the efficacy, safety and plasma exposure of a topically administered TRPV1-antagonist (ACD440 Gel) in healthy subjects. METHODS: The study comprised two parts. In part 1, 24 healthy subjects were included in this randomized double-blind, placebo-controlled, crossover trial. ACD440 Gel or Placebo was applied once daily and wiped off after 1 h, for 5 consecutive days. Assessments were done in normal skin, skin optimized for penetration (by stripping and occlusive gel application) and UVB-irradiated skin. Pain induced by thermo-nociceptive CO2 laser impulses generated laser-evoked potentials (LEPs), with readouts of peak-to-peak (PtP) amplitude in vertex-EEG and pain assessments by VAS (0-100). Endpoints include effects at 1 hour post-dose, AUC(Days 1-5) and AUC(0-24, Day 4). In UVB-irradiated skin, also pain on pinprick and skin redness were assessed. Part 2 explored the plasma pharmacokinetics of ACD440. RESULTS: ACD440 Gel reduced LEP PtP amplitude and VAS pain, p < 0.001, in all skin conditions, versus placebo. In UVB-irradiated skin, pinprick pain was also reduced, p = 0.047. Effects were significant after 1 h, maintaining for at least 9 h. There were no adverse events or drug-induced erythema. Plasma exposures of ACD440 were too low to establish an elimination half-life of ACD400. CONCLUSIONS: Topical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development. SIGNIFICANCE: This study demonstrates that the topical administration of a TRPV1-antagonist, ACD440 Gel, has potential as a new treatment for painful conditions affecting the skin, such as chronic peripheral neuropathic pain, without any local or systemic side effects.

Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects.

BACKGROUND: ACD856 is a positive allosteric modulator of tropomyosin receptor kinase (Trk) receptors which has shown to have pro-cognitive and anti-depressant-like effects in various animal models. It is currently in clinical development for the treatment of Alzheimer's disease and other disorders where cognition is impaired and is also considered for indications such as depression or other neuropsychiatric diseases. ACD856 has a novel mechanism of action modulating the activity of the Trk-receptors, resulting in increased stimulation of the neurotrophin signaling pathways. Previous studies applying single intravenous and oral doses of ACD856 indicate that ACD856 is safe and well-tolerated by healthy volunteer subjects, and that it has suitable safety and pharmacokinetic properties for further clinical development. OBJECTIVES: To investigate the safety and tolerability of 7 days of treatment with multiple ascending oral doses of ACD856 in healthy subjects, and to characterize its pharmacokinetic (PK) properties. In addition, pharmacodynamic effects of ACD856 using quantitative electroencephalography (qEEG) as an indicator for central target engagement were assessed. DESIGN: This was a prospective, phase I, double-blind, parallel-group, placebo-controlled, randomized study of the safety, tolerability, PK and pharmacodynamics of multiple ascending oral doses of ACD856 in healthy subjects. ACD856 or placebo were administered in 3 ascending dose cohorts of 8 subjects. Within each cohort, subjects were randomized to receive either ACD856 (n=6) or placebo (n=2). SETTING: The study was conducted at a First-in-Human unit in Sweden. PARTICIPANTS: Twenty-four healthy male and female subjects. INTERVENTION: The study medication was administered as an oral solution, with ACD856 or the same contents without the active ingredient (placebo). The dose levels ranged from 10 mg to 90 mg. ACD856 was administered once daily for 7 days, targeting steady state. MEASUREMENTS: Safety and tolerability assessments included adverse events, laboratory, vital signs, 12-lead electrocardiogram (ECG), physical examination, assessment of stool frequency and questionnaires to assess symptoms of anxiety, depression, as well as suicidal ideation and behavior. In addition, cardiodynamic ECGs were extracted to evaluate cardiac safety. PK parameters were calculated based on measured concentrations of ACD856 in plasma, urine, and cerebrospinal fluid (CSF) samples. Metabolite profiling, characterization and analysis was performed based on and urine samples. qEEG was recorded for patients in the two highest dose cohorts (30 and 90 mg/day) as a pharmacodynamic assessment to explore central target engagement. RESULTS: Treatment with ACD856 was well tolerated with no serious adverse events. No treatment emergent or dose related trends were observed for any of the safety assessments. ACD856 was rapidly absorbed and reached maximum plasma exposure at 30 to 45 minutes after administration. Steady state was reached before Day 6, with an elimination half-life at steady state of approximately 20 hours. At steady state, ACD856 exhibited accumulation ratios for Cmax and AUC of approximately 1.6 and 1.9 respectively. The exposure, Cmax and AUC0-24, increased proportionally with the dose. There was no unchanged ACD856 detected in urine. The metabolic pattern in urine and plasma was similar, and in alignment with the metabolites observed in preclinical toxicology studies. The level of ACD856 measured in CSF at steady state increased with dose, indicating Central Nervous System (CNS) exposure at relevant levels for pharmacodynamic effects. ACD856 demonstrated significant dose-dependent treatment-associated changes on qEEG parameters. Specifically, increase of the relative theta power and decrease of the fast alpha and beta power was observed, leading to an acceleration of the delta+theta centroid and an increase in the theta/beta ratio. CONCLUSIONS: ACD856 was well tolerated at the tested dose levels (10-90 mg/daily for 7 days) in healthy subjects. The compound has a robust pharmacokinetic profile, with rapid absorption and dose-dependent exposure. ACD856 was shown to pass the blood-brain-barrier, reach relevant exposure in the CNS and to induce dose-dependent treatment-related changes on qEEG parameters, indicating central target engagement.

Clinical testing of three novel transient receptor potential cation channel subfamily V member 1 antagonists in a pharmacodynamic intradermal capsaicin model.

BACKGROUND: The transient receptor potential cation channel subfamily V 1 (TRPV1) is involved in nociception and has thus been of interest for drug developers, as a target for novel analgesics. However, several oral TRPV1 antagonists have failed in development, and novel approaches to target TRPV1 with innovative chemistry are needed. METHOD: This work describes an intradermal microdosing approach in humans for pharmacodynamic deductions and pharmacological profiling of compounds. First, a human capsaicin model was developed, to generate pharmacodynamic translational data (Study Part A, n = 24). Then, three small molecule TRPV1 antagonists (AZ11760788, AZ12048189 and AZ12099548) were investigated in healthy volunteers (Study Part B, n = 36), applying the established model. Pain and flare were assessed by Visual Analogue Score and laser Doppler, respectively. RESULTS: The developed model proved useful for pharmacologic deductions; all compounds caused a dose-dependent inhibition of capsaicin-induced pain and flare responses, with a rank order potency of AZ11760788 > AZ12048189 â‰« AZ12099548. In addition, the dose-response data showed that the minimal antagonist concentrations needed to inhibit TRPV1 was ≥6-7 times the equilibrium dissociation constant for each compound. CONCLUSION: With careful design of a pharmacodynamic translational human pain model, it was possible to rank order TRPV1 efficacy among three investigational TRPV1 antagonists, and to estimate human efficacious concentrations. SIGNIFICANCE: This fast and cost-effective translational approach allows for generation of human target engagement information early in drug development. This could be of value for other development programmes where pharmacological targets are expressed in peripheral sensory nerves.

Pain thresholds, supra-threshold pain and lidocaine sensitivity in patients with erythromelalgia, including the I848Tmutation in NaV 1.7.

OBJECTIVES: Nociceptive thresholds and supra-threshold pain ratings as well as their reduction upon local injection with lidocaine were compared between healthy subjects and patients with erythromelalgia (EM). METHODS: Lidocaine (0.25, 0.50, 1.0 or 10 mg/mL) or placebo (saline) was injected intradermally in non-painful areas of the lower arm, in a randomized, double-blind manner, to test the effect on dynamic and static mechanical sensitivity, mechanical pain sensitivity, thermal thresholds and supra-threshold heat pain sensitivity. RESULTS: Heat pain thresholds and pain ratings to supra-threshold heat stimulation did not differ between EM-patients (n = 27) and controls (n = 25), neither did the dose-response curves for lidocaine. Only the subgroup of EM-patients with mutations in sodium channel subunits NaV 1.7, 1.8 or 1.9 (n = 8) had increased lidocaine sensitivity for supra-threshold heat stimuli, contrasting lower sensitivity to strong mechanical stimuli. This pattern was particularly clear in the two patients carrying the NaV 1.7 I848T mutations in whom lidocaine's hyperalgesic effect on mechanical pain sensitivity contrasted more effective heat analgesia. CONCLUSION: Heat pain thresholds are not sensitized in EM patients, even in those with gain-of-function mutations in NaV 1.7. Differential lidocaine sensitivity was overt only for noxious stimuli in the supra-threshold range suggesting that sensitized supra-threshold encoding is important for the clinical pain phenotype in EM in addition to lower activation threshold. Intracutaneous lidocaine dose-dependently blocked nociceptive sensations, but we did not identify EM patients with particular high lidocaine sensitivity that could have provided valuable therapeutic guidance. SIGNIFICANCE: Acute pain thresholds and supra-threshold heat pain in controls and patients with erythromelalgia do not differ and have the same lidocaine sensitivity. Acute heat pain thresholds even in EM patients with the NaV 1.7 I848T mutation are normal and only nociceptor sensitivity to intradermal lidocaine is changed. Only in EM patients with mutations in NaV 1.7, 1.8 or 1.9 supra-threshold heat and mechanical pain shows differential lidocaine sensitivity as compared to controls.

Systematic review: instruments to assess abdominal pain in irritable bowel syndrome.

BACKGROUND: Consensus on standard methods to assess chronic abdominal pain in patients with irritable bowel syndrome (IBS) is currently lacking. AIM: To systematically review the literature with respect to instruments of measurement of chronic abdominal pain in IBS patients. METHODS: Systematic literature search was performed in PubMed/Medline databases for studies using pain measurement instruments in patients with IBS. RESULTS: One hundred and ten publications were reviewed. A multitude of different instruments is currently used to assess chronic abdominal pain in IBS patients. The single-item methods, e.g. the validated 10-point numeric rating scale (NRS), and questionnaires assessing gastrointestinal symptoms severity, focus mostly on the assessment of only the intensity of abdominal pain. Of these questionnaires, the validated IBS-Symptom Severity Scale includes the broadest measurement of pain-related aspects. General pain questionnaires and electronic momentary symptom assessment tools have been used to study abdominal pain in IBS patients, but have not yet been validated for this purpose. The evidence for the use of provocation tests, e.g. the rectal barostat with balloon distention, for measurement of abdominal pain in IBS is weak, due to the poor correlation between visceral pain thresholds assessed by provocation tests and abdominal pain as assessed by retrospective questionnaires. CONCLUSIONS: The multitude of different instruments to measure chronic abdominal pain in IBS makes it difficult to compare endpoints of published studies. There is need for validated instruments to assess chronic abdominal pain in IBS patients, that overcome the limitations of the currently available methods.

Experimental design and reporting standards for improving the internal validity of pre-clinical studies in the field of pain: Consensus of the IMI-Europain consortium.

Background and aims Pain is a subjective experience, and as such, pre-clinical models of human pain are highly simplified representations of clinical features. These models are nevertheless critical for the delivery of novel analgesics for human pain, providing pharmacodynamic measurements of activity and, where possible, on-target confirmation of that activity. It has, however, been suggested that at least 50% of all pre-clinical data, independent of discipline, cannot be replicated. Additionally, the paucity of "negative" data in the public domain indicates a publication bias, and significantly impacts the interpretation of failed attempts to replicate published findings. Evidence suggests that systematic biases in experimental design and conduct and insufficiencies in reporting play significant roles in poor reproducibility across pre-clinical studies. It then follows that recommendations on how to improve these factors are warranted. Methods Members of Europain, a pain research consortium funded by the European Innovative Medicines Initiative (IMI), developed internal recommendations on how to improve the reliability of pre-clinical studies between laboratories. This guidance is focused on two aspects: experimental design and conduct, and study reporting. Results Minimum requirements for experimental design and conduct were agreed upon across the dimensions of animal characteristics, sample size calculations, inclusion and exclusion criteria, random allocation to groups, allocation concealment, and blinded assessment of outcome. Building upon the Animals in Research: Reportingin vivo Experiments (ARRIVE) guidelines, reporting standards were developed for pre-clinical studies of pain. These include specific recommendations for reporting on ethical issues, experimental design and conduct, and data analysis and interpretation. Key principles such as sample size calculation, a priori definition of a primary efficacy measure, randomization, allocation concealments, and blinding are discussed. In addition, considerations of how stress and normal rodent physiology impact outcome of analgesic drug studies are considered. Flow diagrams are standard requirements in all clinical trials, and flow diagrams for preclinical trials, which describe number of animals included/excluded, and reasons for exclusion are proposed. Creation of a trial registry for pre-clinical studies focused on drug development in order to estimate possible publication bias is discussed. Conclusions More systematic research is needed to analyze how inadequate internal validity and/or experimental bias may impact reproducibility across pre-clinical pain studies. Addressing the potential threats to internal validity and the sources of experimental biases, as well as increasing the transparency in reporting, are likely to improve preclinical research broadly by ensuring relevant progress is made in advancing the knowledge of chronic pain pathophysiology and identifying novel analgesics. Implications We are now disseminating these Europain processes for discussion in the wider pain research community. Any benefit from these guidelines will be dependent on acceptance and disciplined implementation across pre-clinical laboratories, funding agencies and journal editors, but it is anticipated that these guidelines will be a first step towards improving scientific rigor across the field of pre-clinical pain research.

Psychometric evaluation of ADAS-Cog and NTB for measuring drug response.

AIMS: To conduct a psychometric analysis to determine the adequacy of instruments that measure cognition in Alzheimer's disease trials. BACKGROUND: Both the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog) and the Neuropsychological Test Battery (NTB) are validated outcome measures for clinical trials in Alzheimer's disease and are approved also for regulatory purposes. However, it is not clear how comparable they are in measuring cognitive function. In fact, many recent trials in Alzheimer's disease patients have failed and it has been questioned if ADAS-Cog still is a sensitive measure. MATERIALS AND METHODS: The present paper examines the psychometric properties of ADAS-Cog and NTB, based on a post hoc analysis of data from a clinical trial (NCT01024660), which was conducted by AstraZeneca, in mild-to-moderate Alzheimer's disease (AD) patients, with a Mini Mental State Examination (MMSE) Total score 16-24. Acceptability, reliability, different types of validity and ability to detect change were assessed using relevant statistical methods. Total scores of both tests, as well as separate domains of both tests, including the Wechsler Memory Scale (WMS), Rey Auditory Verbal Learning Test (RAVLT) and Delis-Kaplan Executive Function System (D-KEFS) Verbal Fluency Condition, were analyzed. RESULTS: Overall, NTB performed well, with acceptable reliability and ability to detect change, while ADAS-Cog had insufficient psychometric properties, including ceiling effects in 8 out of a total of 11 ADAS-Cog items in mild AD patients, as well as low test-retest reliability in some of the items. DISCUSSION: Based on a direct comparison on the same patient sample, we see advantages of the NTB compared with the ADAS-Cog for the evaluation of cognitive function in the population of mild-to-moderate AD patients. The results suggest that not all of ADAS-Cog items are relevant for both mild and moderate AD population. CONCLUSIONS: This validation study demonstrates satisfactory psychometric properties of the NTB, while ADAS-Cog was found to be psychometrically inadequate.

Patients' assessment of 4-week recovery after ambulatory surgery.

BACKGROUND: patients' own assessment of recovery after ambulatory surgery has not been well studied. The aim was to study patients' self-assessed recovery, the occurrence and time course of post-operative problems in relation to the type of ambulatory surgery. METHODS: a questionnaire was filled in by 355 patients at five time points: pre-operative, first day at home, 1, 2 and 4 weeks post-operatively. Consecutive patients who underwent either inguinal hernia repair (IHR), arthroscopic procedures (AS) or cosmetic breast augmentation (CBA) were included. RESULTS: unplanned return to hospital was rare (3/355). Health care contacts were noted for 9% of the patients during the first week; a total of 70 contacts occurred during the entire period. Pain was the most frequently reported symptom; 40% of the patients reported pain or mobility problems at 1 week, 28% after 2 weeks and 20% after 4 weeks. Pre-operative pain was associated with an increased level of pain during the early post-operative course, in the recovery room and at 1 week post-operatively. IHR was associated with an overall rapid recovery, while AS patients experienced a slower restitution. All AS patients who reported pain after 4 weeks had reported pain problems already pre-operatively. Pain was not present pre-operatively in the CBA group, but was common at 1 and 2 post-operative weeks and was still reported by 11% at 4 weeks. CONCLUSION: self-assessed recovery was found to cover several weeks with procedure-specific recovery patterns. Pain and mobility impairment were still frequently reported 4 weeks post-operatively.

Patient assessed health profile: a six-month quality of life questionnaire survey after day surgery.

AIM: Patient assessed quality of life is one of the principal end-points after day surgery. The aim of the present study was to describe the natural course, differences and timing of final evaluation for three common day surgical procedures; inguinal hernia repair (IHR), arthroscopic procedures (AS); and cosmetic breast augmentation (CBA). METHOD: A total of 355 patients prospectively completed an extended eight-item EQ-5D questionnaire (pain, mobility, mood, self-care, activities, sleep, sex, need for analgesic), preoperatively and at one, three and six months postoperatively. RESULTS: Pain and mobility problems were frequently reported prior to surgery among IHR and AS patients, while CBA patients had less deviation from normal in the preoperative health profile. The proportions of patients reporting surgery-related deviations were 35%, 20% and 5% at one, three and six months respectively. After one month, 50% of AS patients still suffered subjective discomfort as compared to 13% and 20% of the IHR and CBA patients, respectively. Pain and ambulation problems were the most common symptoms in all groups. Six months after surgery, 94% of IHR, 89% of AS and 97% of CBA patients were fully recovered. CONCLUSIONS: No major morbidity or severe complications were observed and patients' satisfaction was high overall. We found procedure-specific changes in the postoperative health profile after day surgery. AS patients recovered more slowly compared with IHR and CBA patients. We conclude that time for final evaluation differs significantly between procedures.

Nabilone produces marked impairments to cognitive function and changes in subjective state in healthy volunteers.

This was a double-blind, randomised, placebo-controlled, crossover study of the acute cognitive and subjective effects of nabilone 1-3 mg in healthy male volunteers. The Cognitive Drug Research computerised system (CDR system) was used to assess changes in attention, working and episodic memory. In addition, a number of self-ratings were conducted including those of mood, alertness and perceived drug effects. Impairments to attention, working and episodic memory and self-ratings of alertness were evident. Volunteers also experienced a number of subjective drug effects. These data demonstrate that acute doses of nabilone in the range 1-3 mg produce clear cognitive and subjective effects in healthy volunteers, and therefore they may be used as reference data in the future study of peripherally acting cannabinoids believed to be free from such effects.

Postoperative impact of regular tobacco use, smoking or snuffing, a prospective multi-center study.

BACKGROUND: The aim was to study the effects of different tobacco administration routes on pain and post-operative nausea and vomiting (PONV), following three common day surgical procedures: cosmetic breast augmentation (CBA), inguinal hernia repair (IHR) and arthroscopic procedures (AS). We have prospectively investigated the effects of regular tobacco use in ambulatory surgery. METHODS: The 355 allocated patients were followed during recovery and the first day at home. RESULTS: Thirty-two percent of the patients used tobacco regularly, 33% of CBA, 27% of IHR and 34% of AS. Pain was well controlled in the post-anesthesia care unit at rest; during ambulation, 37% of all patients reported VAS>3. Tobacco use had no impact on early post-operative pain. Post-operative nausea was experienced by 30% of patients during recovery while in hospital. On day 1, 14% experienced nausea. We found a significant reduction of PONV among tobacco users (smoking and/or snuffing). Smoking or snuffing reduced the risk of PONV by nearly 50% in both genders on the day of surgery and at the first day at home. The reduction of PONV was equal, regardless of tobacco administration routes. CONCLUSION: We found that regular use of tobacco, both by smoking and snuffing, had a significant effect on PONV during the early post-operative period. Non-tobacco users undergoing breast surgery were found to have the highest risk for PONV. We could not see any influence of nicotine use on post-operative pain. Thus, it seems of value to identify regular tobacco use, not only smoking, as a part of the pre-operative risk assessment.

Caffeine does not attenuate experimentally induced ischemic pain in healthy subjects.

BACKGROUND AND AIMS: Caffeine is likely the most widely used psychoactive substance in the world. It is also an analgesic adjuvant and has individual analgesic properties. The latter effect has been attributed to adenosine receptor antagonism, but the site of action is unknown. The aim of this study was to investigate the analgesic properties of caffeine on experimentally induced ischemic pain and to attempt to elucidate whether the site of action is central or peripheral. MATERIALS AND METHODS: Seventeen healthy subjects received intravenous (i.v.) regional and systemic infusions of caffeine at 10 mg/kg or placebo in a double-blind, crossover fashion to investigate the site of action for caffeine-induced analgesia. Subjects underwent a sub-maximum effort tourniquet test. Pain scores [visual analogue scale (VAS), 0-100] were assessed every minute up to a maximum of 45 min. RESULTS: The sum of pain scores (SPS, accumulation of VAS scores) was attenuated neither by systemic 2405 (+/-234) nor by i.v. regional caffeine 2427 (+/-190) as compared with placebo 2442 (+/-205), P=0.99 (mean+/-SEM). Time to maximal VAS score did not differ significantly between treatments, P=0.94. There was no correlation between caffeine concentration in plasma and time to maximal pain score, or between SPS and plasma concentration. CONCLUSION: Caffeine does not have an analgesic effect on ischemic pain, either by a peripheral or by a central site of action.

Clinical practice and routines for day surgery in Sweden: implications for improvement in nursing interventions.

The purpose of this study was to examine nursing practice in day surgery settings in Sweden. A questionnaire focusing on the routines of the day surgery process of patients in Sweden was administered. Based on these findings, appropriate nursing interventions are outlined and discussed. Day surgery routines were in accordance with general worldwide practice. The study revealed that nursing involvement was rare in the preoperative routine. In addition, the major part of the recovery process, including assessments of discharge eligibility and information about pain management, was managed by PACU nurses. The nurse follow-up revealed a number of subjective queries and symptoms that, in a seemingly easy way, could have been prevented by further perianesthesia/perioperative patient education. There is an obvious place for nursing interventions when the decision for day surgery is taken. These interventions should focus on providing the patient with information before surgery, preoperative patient health screening, and information/education at discharge. Furthermore, nursing interventions should include quality assurance, such as follow-up calls for the evaluation of care, as well as providing information and coaching for the patient at home.

Children in day surgery: clinical practice and routines. The results from a nation-wide survey.

BACKGROUND: Day surgery is common in paediatric surgical practice. Safe routines including parental and child information in order to optimise care and reduce anxiety are important. Most day surgery units are not specialised in paediatric care, which is why specific paediatric expertise is often lacking. METHODS: We studied the practice of paediatric day surgery in Sweden by a questionnaire survey sent to all hospitals, obtaining an 88% response rate. Three specific paediatric cases were enquired for in more detail. RESULTS: The proportion of paediatric day surgery vs. in-hospital procedures was 46%. Seventy-one out of 88 responding units performed paediatric day surgery. All units had anxiolytic pre-medication as a routine in 1-6-year-olds, and in 7-16-year-olds at 60% of the units. Most units performed circumcision and adenoidectomy, while 33% performed tonsillectomy. Anaesthesia induction was intravenous in older children, and also in 1-6-year-olds at 50% of the units. Parental presence at induction was mandatory. Post-operatively, 93% of units routinely assessed pain. Paracetamol and NSAIDs were the most common analgesics, as monotherapy or combined with rescue medication in the recovery as IV morphine. At 42% of units, take-home bags of analgesics were provided, covering 1-3 days of treatment. Pain was the most frequent complaint on follow-up. Micturition difficulties were common after circumcision, nausea after adenoidectomy and nutrition difficulties after tonsillectomy. CONCLUSIONS: In Sweden, most day surgery units perform paediatric surgery, most children receive pre-medication, anaesthesia is induced IV and take-home analgesics paracetamol and or NSAIDs are often provided. Still, pain is a common complaint after discharge.

Clinical practice and routines for day surgery in Sweden: results from a nation-wide survey.

BACKGROUND: Day surgery has expanded considerably during the last decades. Routines and standards have developed but differ between and within countries. METHODS: We studied the practice of day surgery in Sweden by an extensive questionnaire survey sent to all 92 hospitals. RESULTS: The proportion of day surgery vs. in-hospital procedures was overall 43%, with 43% in adults and 46% in children. Orthopaedic (33%), general (29%) and gynaecological (17%) surgery were the most common ambulatory procedures. Most patients (>90%) underwent pre-operative assessment by an anaesthesiologist. Patient self-assessment questionnaires were common (86%). Risk stratification for post-operative nausea and vomiting was used by 70% of the departments. Anxiolytic pre-medication was uncommon. Most anaesthesiologists (95%) used pre-operative oral analgesics to initiate post-operative analgesia, the most common being paracetamol (95%), NSAIDs (73%) and coxibs (15%). A balanced general anaesthesia technique was preferred. Post-operatively, 93% of the units routinely assessed patients' pain. Analgesic combinations of paracetamol, NSAIDs and weak opioids were used by 94% of the units. Most hospitals (80%) had standardised discharge criteria based on clinical assessment, and many required a patient escort at home for 24 h post-operatively. Assessments of unplanned admission, re-admission and post-operative complications were not performed routinely. Follow-up telephone calls within 1-2 days were performed regularly in about 40% of the units, or in selected patients only (37%). Pain was the most frequent complaint on follow-up. CONCLUSIONS: In Sweden, a high degree of standardised regime for day surgical practice was found. Post-operative pain is the most common complaint after discharge.

Multiple dose gabapentin attenuates cutaneous pain and central sensitisation but not muscle pain in healthy volunteers.

Various muscle pains constitute a large clinical problem, both for patients and clinicians. Gabapentin is an established therapy in neuropathic pain and reduces cutaneous pain in healthy volunteers. Gabapentin in combination with other analgesics reduces post-operative pain. No data exist on the effect of gabapentin on muscle pain. This study investigates the effect of gabapentin on muscle and cutaneous pain in healthy volunteers. Sixteen healthy volunteers, 8 male/8 female, were included in this double-blind three-session crossover study comparing the effects of 0, 1200, 1800 and 2600 mg (pre-treatment, titrated over 4 doses) gabapentin and placebo. Muscle pain was induced by infusing 0.5 ml of hypertonic saline into the anterior tibial muscle. Simultaneously, subjects graded pain on a computerized visual analog scale (VAS, 0-10). Total (AUC, VAS*duration in s) and maximal pain (VAS(max)) were assessed. Areas of local and referred pain were measured. Further, continuous intracutaneous electrical stimulation was applied to the forearm. Current was increased until pain intensity 5/10 or until subjects reached a cut-off of 70 mA. Spontaneous pain (VAS 0-10), areas of secondary hyperalgesia to pinprick (cm2) and mechanical pain threshold (g) within this area were assessed. Gabapentin pre-treatment reduced sensitivity to electrical induction of skin pain by 14%, p=0.016. Secondary hyperalgesia was induced, but areas were reduced after pre-treatment, p<0.05. Mechanical pain thresholds were unaffected. Pain induced by intramuscular infusion of hypertonic saline was not affected by gabapentin. In conclusion, single or repeated dosing of gabapentin reduced cutaneous but not muscle pain in healthy volunteers.

Intrathecal adenosine increases spinal cord blood flow in the rat: measurements with the laser-Doppler flowmetry technique.

BACKGROUND: Adenosine and adenosine analogues induce antinociception both after systemic and intrathecal (i.t.) administration in animal models. Further, patients with neuropathic pain have been treated successfully with i.t. adenosine. Prior to introducing new analgesic drugs for regular spinal use in humans, experimental studies must be undertaken to evaluate the risks of neurotoxicity. It is important to evaluate the possibility of cytotoxic effects and that antinociception may be due to decreased spinal cord blood flow (SCBF) and neural ischaemia. The present study evaluates whether adenosine or isotonic mannitol induces changes in SCBF as assessed by laser-Doppler flowmetry (LDF). METHODS: After laminectomy and insertion of i.t. catheters, seven rats received adenosine 50 microg in isotonic mannitol 500 microg, six rats received isotonic mannitol 500 microg and eight rats received saline 0.9%. SCBF was registered by the LDF technique continuously for 3 h after injection. Arterial blood pressure was also assessed. RESULTS: In the adenosine in mannitol group, SCBF increased up to 230% of baseline levels for almost 40 min, P = 0.044 and then declined. In the mannitol group, SCBF increased up to 180% of baseline (P < 0.011) before declining. At 60 min, SCBF had returned to saline levels and remained stable during the rest of the experiment. CONCLUSION: Intrathecal administration of adenosine in mannitol and of mannitol both increased SCBF in rats, compared with saline. It is unlikely that the effects on SCBF induced by adenosine and mannitol could result in neurotoxicity of the spinal cord.

Experimentally induced ischaemic pain in healthy humans is attenuated by the adenosine receptor antagonist theophylline.

AIMS: Endogenous adenosine is considered a prominent pain mediator in ischaemia. In contrast, it has been shown that exogenous adenosine can reduce tourniquet induced ischaemic pain in healthy volunteers. The aim of this study was to investigate if pharmacological antagonism of endogenous adenosine actions with an intravenous infusion of theophylline could attenuate experimentally induced ischaemic pain. METHODS: Nineteen healthy volunteers, 11 males, eight female, received theophylline 7 mg kg-1 or placebo intravenously, in a randomized, double blind and crossover fashion, prior to a sub-maximum effort forearm tourniquet test. Experiments were carried out with 1-week intervals to avoid pre-conditioning. Pain scores [visual analogue scale (VAS), 0-100] were assessed every minute up to a maximum of 30 min. RESULTS: The sum of pain scores (accumulation of VAS scores) was attenuated by theophylline, 691 [200-1550 (median and 25-75% percentiles)], compared with placebo, 1231 (545-1675), P < 0.001. Also, peak VAS pain was lower during theophylline treatment, 48 +/- 38 (mean +/- SD), compared with placebo, 74 +/- 27, P < 0.001. Blood pressure increased during the experiment with no difference between treatments. Heart rate was not affected by tourniquet or drug treatment. CONCLUSIONS: It is concluded that the adenosine receptor antagonist theophylline is able to attenuate the development of ischaemia pain during experimental ischaemia in humans. This implies a role for adenosine as both facilitatory mediator and a modulator of ischaemia skeletal muscle pain.

Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil and ketamine in healthy volunteers.

BACKGROUND: Muscle pain is a major clinical problem but the underlying mechanisms and its pharmacological modulation need further investigation. This study on 15 volunteers evaluates if two experimental muscle pain models are sensitive to micro -receptor agonists and to an N-methyl-D-aspartate (NMDA)-receptor antagonist. METHODS: In the left tibialis anterior, intramuscular electrical (IMES) pain thresholds were determined for single (SPTmuscle) and five (RPTmuscle) repeated stimuli. Also pain to suprathreshold stimulation at 150% of RPTmuscle, 10 s, was assessed on a visual analog scale (VAS) as AUCimes (area under the VAS curve). In the right TA muscle, pain intensity on infusion of 0.5 ml of hypertonic saline, 5% (AUCsaline) and pain distribution indicated as local and referred were evaluated. Pain variables were assessed before, during and after intravenous infusions of morphine (10 microg x kg-1 min-1, 10 min), alfentanil (target-controlled infusion, plasma concentration; 60 ng ml-1, 60 min) and ketamine (10 microg x kg-1 min-1, 60 min). All data were normalized to baseline pain values (before drug infusions were initiated) and compared with placebo (midazolam, 2 microg x kg-1 min-1, 10 min). RESULTS: SPTmuscle increased (log mean values +/- SD, mA) with morphine (0.11 +/- 0.17, P < 0.05), alfentanil (0.28 +/- 0.24, P < 0.001) and ketamine (0.19 +/- 0.18, P < 0.01) as compared with placebo (-0.03 +/- 0.12). Alfentanil and ketamine also increased RPTmuscle (0.25 +/- 0.21, P < 0.01 and 0.21 +/- 0.19, P < 0.05, respectively) as compared with placebo (0.00 +/- 0.17). Pain to IMES (AUCimes) was reduced (median values [25th-75th percentiles], cm x s) by alfentanil and ketamine (-19.7 [-14.6 - -29.6] and-12.8 [-8.3 - -27.8], P < 0.05, respectively) vs. placebo (-0.8 [1.6 - -12.3]). Similar drug effects were seen when pain to infusion of hypertonic saline (AUCsaline) was assessed (alfentanil:-388 [-99 - -677] and ketamine:-326 [-227 - -573], P < 0.05 compared with placebo: 150 [449--240]). Ketamine also reduced the size of the local pain area (-58.4 [-21.2 - -176.1], < 0.05) as compared with placebo (-0.4 [70.6 - -13.4]). The frequency of referred pain was also lower when ketamine was given (3/13, P < 0.05) vs. placebo (9/14). CONCLUSION: The study demonstrates that experimental muscle pain induced in humans by electrical stimulation and infusion of hypertonic saline is sensitive to pharmacological modulation similar to preclinical animal tests and clinical trials. The data suggest that these models can be valuable tools in analgesic drug development.

A randomised double-blind evaluation of adenosine as adjunct to sufentanil in spinal labour analgesia.

BACKGROUND: Intrathecal injection of sufentanil offers labour pain relief of short duration. This double-blind randomised study evaluates if the combination of adenosine to sufentanil could give relevant prolongation (40%) of the duration of sufentanil spinal analgesia. METHODS: Twenty-five healthy parturients requesting labour analgesia were included. Patients received 10 micro g of sufentanil + 500 micro g of adenosine or 10 micro g of sufentanil intrathecally. Pain intensity and duration of pain relief were assessed. RESULTS: Pain relief was equal between groups. Duration of analgesia was not increased by adenosine + sufentanil, 99 +/- 54 min, vs. sufentanil, 89 +/- 56 min. CONCLUSION: Adding 500 micro g of adenosine to 10 micro g of sufentanil could not provide any prolongation of labour pain relief.