Cannabinoid effects on ventilation and breathlessness: a pilot study of efficacy and safety.

Based on the neurophysiology of dyspnoea and the distribution of cannabinoid receptors within the central nervous system, we hypothesize that the unpleasantness of breathlessness will be ameliorated in humans by cannabinoids, without respiratory depression. Five normal and four chronic obstructive pulmonary disease (COPD) subjects entered a double blind, randomized, placebo-controlled crossover study with two test days. Subjects received sublingual cannabis extract or placebo. A maximum of 10.8 mg tetrahydrocannabinol and 10 mg cannabidiol were given. Breathlessness was simulated using fixed carbon dioxide loads. Measurements taken were of breathlessness (visual analogue scale [VAS] and breathlessness descriptors), mood and activation, end-tidal carbon dioxide tension and ventilatory parameters. These were measured at baseline and 2 hours post placebo and drug administration. Normal and COPD subjects showed no differences in breathlessness VAS scores and respiratory measurements before and after placebo or drug. After drug administration, COPD subjects picked 'air hunger' breathlessness descriptors less frequently compared to placebo. We have shown that breathlessness descriptors may detect an amelioration of the unpleasantness of breathlessness by cannabinoids without a change in conventional breathlessness ratings (VAS). A stimulus more specific for air hunger may be needed to demonstrate directly a drug effect on breathlessness. However, this study shows that the inclusion of respiratory descriptors may contribute to the assessment of drug effects on breathlessness.

The gender imbalance in academic medicine: a study of female authorship in the United Kingdom.

OBJECTIVES: A shortfall exists of female doctors in senior academic posts in the United Kingdom. Career progression depends on measures of esteem, including publication in prestigious journals. This study investigates gender differences in first and senior authorship in six peer-reviewed British journals and factors that are associated with publication rates. DESIGN AND MAIN OUTCOME MEASURES: Data was collected on United Kingdom first and senior authors who had published in the British Medical Journal, Lancet, British Journal of Surgery, Gut, British Journal of Obstetrics and Gynaecology and the Archives of Diseases in Childhood. Authorship and gender were quantified for 1970, 1980, 1990, 2000 and 2004 (n=6457). In addition, selected questions from the Athena Survey of Science Engineering and Technology (ASSET2006), web-based doctor's self-report of publications were also analysed (n=1162). RESULTS: Female first authors increased from 10.5% in 1970 to 36.5% in 2004 (p<0.001) while female senior authors only increased from 12.3% to 16.5% (p=0.046). Within individual journals, the largest rise was in British Journal of Obstetric and Gynaecology with 4.5- and 3-fold increases for first and senior authors, respectively. In contrast, female senior authors marginally declined in Gut and Lancet by 2.8% and 2.2%, respectively. ASSET2006 identified that female respondents who were parents were less likely to have publications as sole (p=0.02) and joint authors (p<0.001) compared to male respondents. Female respondents with care responsibilities for parents/partner also had less publications as lead authors compared to those without carer responsibilities (p<0.001). CONCLUSION: The increase in UK female first authors is encouraging. In contrast, there is considerable lag and in some specialties a decline in female senior authors. Factors that could narrow the gender gap in authorship should be sought and addressed.

Local anaesthetic drugs: adverse effects as reported through the ADROIT system in the UK.

PURPOSE: Adverse drug reactions (ADRs) to local anaesthetic drugs are reported voluntarily through the Adverse Drug Reporting On Line Tracking system (ADROIT). We aimed to determine hazards associated with drugs commonly used in anaesthesia including ropivacaine and levobupivacaine. METHODS: The ADROIT database was queried for all ADRs to local anaesthetics used in anaesthesia and surgery between 1967 and 2005. Details of age, sex, suspect drug, date and reaction details were analysed. RESULTS: There were 985 reports analysed, 797 for lidocaine, 160 for bupivacaine, 16 for ropivacaine and 12 for levobupivacaine. The female to male ratio was 1.6:1 and age was not a factor determining the frequency of reactions. A vasoconstrictor was included in the lidocaine formulation in 27% of reports. When methylprednisolone (Depo-Medrone) or prilocaine (as EMLA cream) were used in combination with lidocaine, the frequency of allergic reports increased significantly (p < 0.0001). Levobupivacaine demonstrated a hazard signal for cardiovascular symptoms. Fatality rate within the reports was higher for bupivacaine (11%) than for lidocaine (3%). CONCLUSIONS: The patient's age and sex were not found to influence the type of reactions reported. Lidocaine with methylprednisolone or prilocaine (as EMLA(TM) cream) generated the largest number of reports of allergic phenomena. Fatalities were most frequently reported in association with bupivacaine.

Gender differences and pain medication.

Subtle genetic and psychological variations are increasingly recognized to contribute to pain and analgesic efficacy and safety. The influence of sex on this relationship remains poorly understood, particularly in humans. The issue is complicated by the overlay of gender onto physical sex, and its associated stereotypes and expectations. Women appear to use more pain-relieving medications than men; however, it remains unclear whether these observations represent true differences in analgesic usage patterns, or reporting bias. Differences in analgesic efficacy relating to body composition, metabolism and hormonal profiles have been demonstrated. Psychological and social elements of gender have also been associated with altered pain experiences and analgesic use profiles, albeit with significant individual variations. Intra-group differences may ultimately prove more important than sex differences. Further research may unravel the various threads linking gender and sex effects on analgesia with the aim of individualizing analgesia to optimize pain relief.

Integrating the dimensions of sex and gender into basic life sciences research: methodologic and ethical issues.

BACKGROUND: The research process -- from study design and selecting a species and its husbandry, through the experiment, analysis, peer review, and publication -- is rarely subject to questions about sex or gender differences in mainstream life sciences research. However, the impact of sex and gender on these processes is important in explaining biological variations and presentation of symptoms and diseases. OBJECTIVE: This review aims to challenge assumptions and to develop opportunities to mainstream sex and gender in basic scientific research. METHODS: Questions about the mechanisms of sex and gender effects were reviewed in relation to biological, environmental, social, and psychological interactions. Gender variations, in respect to aging, socializing, and reproduction, that are present in human populations but are rarely featured in laboratory research were considered to more effectively translate animal research into clinical health care. RESULTS: Methodologic approaches to address the present lack of a gender dimension in research include actively reducing variations through attention to physical factors, biological rhythms, and experimental design. In addition, through genomic and acute nongenomic activity, hormones may compound effects through multiple small sex differences that occur during the course of an acute pathologic event. Furthermore, the many exogenous sex steroid hormones and their congeners used in medicine (eg, in contraception and cancer therapies) may add to these effects. CONCLUSIONS: The studies reviewed provide evidence that sex and gender are determinants of many outcomes in life science research. To embed the gender dimension into basic scientific research, a broad approach -- gender mainstreaming -- is warranted. One example is the use of review boards (eg, animal ethical review boards and journal peer-review boards) in which gender-related standardized questions can be asked about study design and analysis. A more fundamental approach is to question the relevance of present-day laboratory models to design methods to best represent the age-related changes, comorbidity, and variations experienced by each sex in clinical medicine.

Studying sex and gender differences in pain and analgesia: a consensus report.

In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?"

Women in the UK academic medicine workforce.

OBJECTIVES: This study aimed to compare data on the employment profiles (such as grade, place of work, etc.) of male and female clinical academics. METHODS: We carried out a comparative review of workforce data within academic medicine for 2004 and 2005, pertaining to the workforce in all specialties in UK medical schools. RESULTS: We identified 3255 and 3365 lecturers, senior lecturers, readers and professors in 2004 and 2005, respectively, of whom 21% were women. In 2004 and 2005, 12% and 11%, respectively, of 1157 and 1364 UK medical professors were women. The number of women filling such positions in individual schools ranged from 0% to 33% across schools. The total numbers of women post-holders and their full-time equivalents were similar, indicating that the majority of posts were full-time. CONCLUSIONS: In England only 1 in 10 medical clinical professors are women. At the onset of the study period, 6 medical schools employed no female professors, with a consequent lack of female role models at these institutions. Large variations between schools suggest that some workforce practices may be detrimental to women's academic careers.

Results of forty years Yellow Card reporting for commonly used perioperative analgesic drugs.

BACKGROUND: A variety of analgesics are used perioperatively and associated adverse drug reactions (ADRs) may complicate anaesthesia and recovery. METHODS: We aimed to measure the demographics of reported suspected ADRs to alfentanil, fentanyl, ketorolac, morphine, nalbuphine, papaveretum, pethidine and remifentanil. We report a retrospective analysis of Yellow Card reports of suspected ADRs from 1965-2004 as classified in the Adverse Drug Reaction On-line Tracking database (ADROIT) of the Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: In total, 1312 reactions were retrieved. A single drug was reported in 908, 39 were fatal and 219 categorised as 'allergic'. Allergic phenomenon varied from 2/33 (6%) for remifentanil to 11/53 (21%) for alfentanil. 'Cardiovascular' reactions were reported frequently with remifentanil (18/33, 55%) and alfentanil (19/53, 36%) and these generated a signal for possible hazards from proportional reporting ratios (PRRs). The opioid fentanyl was associated with similar hazard signals for muscular and psychiatric ADRs. CONCLUSIONS: Perioperative vigilance may reduce morbidity and mortality from preventable ADRs to analgesic drugs. Denominator and diagnostic data are essential for prospective studies.

UK drug analysis prints and anaesthetic adverse drug reactions.

PURPOSE: Anaesthetic drugs were selected from the Medicines and Healthcare products Regulatory Agency Drug Analysis Prints in order to determine the number and types of reported reactions and associated mortality. METHODS: The chosen drug groups were the intravenous induction agents, the neuromuscular blocking drugs and neostigmine, the inhalational anaesthetic agents and nitrous oxide, local anaesthetic agents and a selection of analgesics agents, naloxone and midazolam and its antagonist flumazenil. From each drug file, the number and type of reactions were analysed. Mortality was calculated as a percentage of the number of deaths against patient reports. RESULTS: A total of 11,199 reactions were analysed from 6603 patients of whom 620 (9%) died. Few drug records reported reactions from multiple constituent formulations. The majority of reactions were not allergic. The highest mortality was in the inhalational anaesthetic group. Although the greatest number of fatal events was associated with halothane, this drug is no longer used. Nevertheless the percentage remains high because cardiovascular mortality is still being reported. Local anaesthetic use was associated with the smallest percentage mortality (3%). The highest reported number of reactions was associated with the intravenous induction agents and idiosyncratic neurological and peripheral vascular reactions were linked with the use of etomidate. CONCLUSIONS: The reporting of allergic reactions was low. The data demonstrate that induction of anaesthesia presents the highest risk of adverse drug reaction; there is also mortality from newer drugs for example, desflurane, remifentanil as well as from drugs for which there is no alternative, for example, suxamethonium.

A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management.

BACKGROUND: Cannabinoids have dose-related antinociceptive effects in animals. This clinical study aimed to investigate whether a single oral dose of cannabis plant extract (Cannador; Institute for Clinical Research, IKF, Berlin, Germany) could provide pain relief with minimal side effects for postoperative pain. METHODS: Patients (aged 18-75 yr) were recruited and consented before surgery if patient-controlled analgesia was planned for provision of postoperative pain relief. Each patient received a single dose of 5, 10, or 15 mg Cannador if he or she had at least moderate pain after stopping patient-controlled analgesia. Starting with 5 mg, dose escalation was based on the number of patients requesting rescue analgesia and adverse effects. Pain relief, pain intensity, and side effects were recorded over 6 h and analyzed using tests for trend with dose. RESULTS: Rescue analgesia was requested by all 11 patients (100%) receiving 5 mg, 15 of 30 patient (50%) receiving 10 mg, and 6 of 24 patients (25%) receiving 15 mg Cannador (log rank test for trend in time to rescue analgesia with dose P < 0.001). There were also significant trends across the escalating dose groups for decreasing pain intensity at rest (P = 0.01), increasing sedation (P = 0.03), and more adverse events (P = 0.002). The number needed to treat to prevent one rescue analgesia request for the 10-mg and 15-mg doses, relative to 5 mg, were 2.0 (95% confidence interval, 1.5-3.1) and 1.3 (95% confidence interval, 1.1-1.7), respectively. The study was terminated because of a serious vasovagal adverse event in a patient receiving 15 mg. CONCLUSION: These significant dose-related improvements in rescue analgesia requirements in the 10 mg and 15 mg groups provide a number needed to treat that is equivalent to many routinely used analgesics without frequent adverse effects.

Psychosocial influences on women's experience of planned elective cesarean section.

OBJECTIVE: The successful management of pain from normal or interventional delivery is an important part of women's experience of childbirth. Our objective was to examine psychosocial factors (expectations, control beliefs, anxiety sensitivity) as measured in mothers and birth partners before an elective cesarean section. We focused on the impact that these variables have on maternal fear and pain during and after delivery. METHODS: Sixty-five women booked for an awake cesarean section with a regional nerve block and their birth partners were recruited. Data were collected at three time points for the mothers, before, during the cesarean section and after delivery on the postnatal ward, and at two time points for the birth partners (before and during the cesarean section). RESULTS: Maternal fear responses varied during the operation, in that fear was greatest at the point of administration of the nerve block. Within mothers, preoperative negative expectations were related to fear experiences during delivery, which was in turn related to their postoperative pain. Maternal anxiety sensitivity was found to mediate the relationship between negative expectations and fear, whereas birth partner's fear mediated between maternal fear and postoperative pain. Mothers' prenatal perceptions of control over drugs predicted their postoperative pain. CONCLUSIONS: Maternal fear during cesarean section not only fluctuates, but may be influenced by psychosocial factors, including their birth partner. Psychosocial factors were also important predictors of postoperative experiences. Interventions that appropriately manage psychological and social factors during cesarean delivery may facilitate a more positive experience for mothers.

Adverse effects of neuromuscular blocking agents based on yellow card reporting in the U.K.: are there differences between males and females?

BACKGROUND: Adverse drug reactions (ADRs) are known to occur during anaesthesia; in the U.K. such ADRs may be reported through the Yellow Card Scheme (YCS). Our aim was to determine the demographics of ADRs to neuromuscular blocking drugs without formal causality assessment. METHODS: A retrospective analysis of ADRs to seven neuromuscular blocking drugs reported via the YCS during a greater than 30-year period was performed. Sex and age were analysed in order to identify at risk groups. RESULTS: Of 998 reports, 969 included gender. Non-allergic suspected reactions occurred with almost the same frequency as those with an allergic component. The majority occurred in females 676 (70%), and significant sex differences were measured between drugs. Males were more likely to have suffered an ADR to atracurium (p = 0.01) whilst females experienced more ADRs to suxamethonium (p = 0.01). ADRs proved fatal in 81 (9%) of the 950 reports for single drugs. Mortality following suxamethonium was significantly higher in males at 22% compared with 9% females (p < 0.001). More women than men were reported to have allergic reactions, 73% (362/499) compared with 27% (137/499) respectively. The female:male ratio for ADRs was reversed for subjects < 10 years compared with peak ADR reports during the decade from 31-40 years. CONCLUSIONS: Sex differences in mortality exist in this analysis. The unexpected high frequency of non-allergic ADRs suggests that morbidity and mortality from reactions to established drugs is twice that expected from allergic reactions alone. Standards and guidance for the reporting of ADRs warrant urgent development.

Cannabis use in sickle cell disease: a questionnaire study.

Cannabinoids are increasingly being considered for the management of various painful conditions, and could be considered as an option for treating acute pain in sickle cell disease (SCD). The objective of this study was to determine the extent of use of cannabis in the community for pain and other symptom relief, and its side effects during self-administration in patients with SCD. Patients attending Central Middlesex Hospital in London were invited to complete a structured self-administered anonymous questionnaire. Eighty-six young adults with HbSS, HbSC and HbSbetathalassaemia disease (median age 30 years) participated in the study. Results showed that 31 (36%) had used cannabis in the previous 12 months to relieve symptoms associated with SCD. The main route in all but two patients was by smoking. The main reasons for use were to reduce pain in 52%, and to induce relaxation or relieve anxiety and depression in 39%. Symptoms related to sedation and mood effects were reported in 77% of patients. The majority of patients (58%) expressed their willingness to participate in studies of cannabis as a medicine. We conclude that research in the use of cannabinoids for pain relief in SCD would be both important and acceptable to adult patients.

Cannabis use in HIV for pain and other medical symptoms.

Despite the major benefits of antiretroviral therapy on survival during HIV infection, there is an increasing need to manage symptoms and side effects during long-term drug therapy. Cannabis has been reported anecdotally as being beneficial for a number of common symptoms and complications in HIV infections, for example, poor appetite and neuropathy. This study aimed to investigate symptom management with cannabis. Following Ethics Committee approval, HIV-positive individuals attending a large clinic were recruited into an anonymous cross-sectional questionnaire study. Up to one-third (27%, 143/523) reported using cannabis for treating symptoms. Patients reported improved appetite (97%), muscle pain (94%), nausea (93%), anxiety (93%), nerve pain (90%), depression (86%), and paresthesia (85%). Many cannabis users (47%) reported associated memory deterioration. Symptom control using cannabis is widespread in HIV outpatients. A large number of patients reported that cannabis improved symptom control.

Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain.

BACKGROUND: Breast pain and tenderness affects 70% of women at some time. These symptoms have been attributed to stretching of the nerves with increase in breast size, but tissue mechanisms are poorly understood. METHODS: Eighteen patients (n = 12 breast reduction and n = 6 breast reconstruction) were recruited and assessed for breast pain by clinical questionnaire. Breast skin biopsies from each patient were examined using immunohistological methods with specific antibodies to the capsaicin receptor TRPV1, related vanilloid thermoreceptors TRPV3 and TRPV4, and nerve growth factor (NGF). RESULTS: TRPV1-positive intra-epidermal nerve fibres were significantly increased in patients with breast pain and tenderness (TRPV1 fibres / mm epidermis, median [range] - no pain group, n = 8, 0.69 [0-1.27]; pain group, n = 10, 2.15 [0.77-4.38]; p = 0.0009). Nerve Growth Factor, which up-regulates TRPV1 and induces nerve sprouting, was present basal keratinocytes: some breast pain specimens also showed NGF staining in supra-basal keratinocytes. TRPV4-immunoreactive fibres were present in sub-epidermis but not significantly changed in painful breast tissue. Both TRPV3 and TRPV4 were significantly increased in keratinocytes in breast pain tissues; TRPV3, median [range] - no pain group, n = 6, 0.75 [0-2]; pain group, n = 11, 2 123, p = 0.008; TRPV4, median [range] - no pain group, n = 6, [0-1]; pain group, n = 11, 1 [0.5-2], p = 0.014). CONCLUSION: Increased TRPV1 intra-epidermal nerve fibres could represent collateral sprouts, or re-innervation following nerve stretch and damage by polymodal nociceptors. Selective TRPV1-blockers may provide new therapy in breast pain. The role of TRPV3 and TRPV4 changes in keratinocytes deserve further study.

Phosphorus-31 brain MR spectroscopy in women during and after pregnancy compared with nonpregnant control subjects.

BACKGROUND AND PURPOSE: A reversible decrease in brain size has been demonstrated during normal pregnancy that is maximal at term and returns to normal after many months. The purpose of this longitudinal study was to use phosphorus-31 MR spectroscopy to determine if metabolic changes explain this physiologic event. METHODS: Pregnant women (n = 12) were examined at term and up to 6 months after delivery. Nonpregnant control subjects (n = 7) were imaged twice (a month apart) to exclude hormone effects. Brain (31)P MR spectra were acquired at 1.5 T, and intracellular pH was calculated from the chemical shift between phosphocreatine and inorganic phosphate resonances. Statistical analysis was performed by using an analysis of variance. RESULTS: We found no statistically significant differences in the relative levels of metabolite associated with cerebral bioenergetics and cell membrane metabolism between pregnant women and nonpregnant women. However, a significant increase in cerebral pH was observed in pregnant women at 6 weeks after delivery compared with control subjects (7.074 +/- 0.063 vs 7.017 +/- 0.041; P < .05). pH returned to normal by 6 months after delivery (7.014 +/- 0.010). CONCLUSION: Changes in brain size associated with pregnancy appear to be associated with an increase in intracellular pH after delivery. The observed alkalosis may reflect altered cellular metabolism. These persistent brain perturbations associated with pregnancy indicate that, when postpartum physiologic and pharmacologic changes are measured, long-term effects may be expected in central nervous system processing.