Tag: James Cook University

Background: Pregnant women are at an increased risk of developing influenza. The National Health and Medical Research Council recommends seasonal influenza vaccination for all pregnant women who will be in their second or third trimester during the influenza season. The aim of this review is to explore the views of health care workers regarding seasonal influenza vaccination in antenatal women and describe the barriers in the delivery of the vaccine. Methods: A literature search was conducted using MEDLINE for the terms: “influenza,” “pregnancy,” “antenatal,” “vaccinations,” “recommendations,” “attitudes,” “knowledge” and “opinions”. The review describes findings of publications concerning the inactivated influenza vaccination only, which has been proven safe and is widely recommended. Results: No studies have addressed the knowledge and attitudes of Australian primary health care providers towards influenza vaccination despite their essential role in immunisations in Australia. Overseas studies indicate that factors that contribute to the low vaccination rates are 1) the lack of general knowledge of influenza and its prevention amongst health care workers (HCWs) 2) variable opinions and attitude regarding the vaccine 3) lack of awareness of the national guidelines 4) and lack of discussion of the vaccine by the HCW. Lack of maternal knowledge regarding the safety of the vaccine and the cost-burden of the vaccine are significant barriers in the uptake of the vaccination. Conclusion: Insufficient attention has been given to the topic of influenza vaccinations in pregnancy. Significant efforts are required in Australia to obtain data about the rates of influenza vaccination of pregnant women.

Introduction

Seasonal influenza results in annual epidemics of respiratory diseases. Influenza epidemics and pandemics increase hospitalisation rates and mortality, particularly among the elderly and high risk patients with underlying conditions. [1-3] All pregnant women are at an increased risk of developing influenza due to progressive suppression of Th1- cell-mediated immunity and other physiological changes that cause culmination of morbidity towards the end of pregnancy. [4-7]

Annual influenza vaccination is the most effective method for preventing influenza virus infection and its complications [8] Trivalent inactivated influenza vaccine (TIV) has been proven safe and is recommended for person aged ≥6 months, including those with high- risk conditions such as pregnancy. [8-10] A randomised controlled study in Bangladesh demonstrated that TIV administered in the third trimester of pregnancy resulted in reduced maternal respiratory illness and reduced infant influenza infection. [11, 12] Another randomised controlled trial has shown that influenza immunisation of pregnant women reduced influenza-like illness by more than 30% in both the mothers and the infants, and reduced laboratory-proven influenza infections in 0- to 6-month-old infants by 63%. [13]

The current Australian Immunisation Guidelines recommend routine administration of influenza vaccination for all pregnant women who will be in the second or third trimester during the influenza season, including those in the first trimester at the time of vaccination. [4,14,15] The seasonal influenza vaccination has been made available for free to all pregnant women in Australia since 2010. [4] However, The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZOG) statement for ‘Pre-pregnancy Counselling and routine Antenatal Assessment in the absence of pregnancy Complications’ does not explicitly mention routine delivery of influenza vaccination to healthy pregnant women. [16] RANZCOG recently published the college statement on swine flu vaccination during pregnancy; advising that pregnant women without complications and recent travel history must weigh the risk-benefit ratio before deciding to uptake the H1N1 influenza immunisation. [17] Therefore, it is evident that there is conflicting advice in Australia about the routine delivery of influenza vaccination to healthy pregnant women. In contrast, firm recommendation for routine influenza vaccination for pregnant women was established in 2007, by the National Advisory Committee on Immunisations (NACI) in Canada, with minimal conflict from The Society of Obstetricians and Gynaecologists of Canada (SOGC). [6] Succeeding the 1957 influenza pandemic, the rate of influenza immunisations increased significantly with greater than 100,000 women receiving the vaccination annually between 1959-1965 in the United States. [8] Since 2004 the American Advisory Committee on Immunisation Practice (ACIP) has recommended influenza vaccination for all pregnant women, at any stage of gestation. [9] This is supported by The American College of Obstetricians and Gynaecologists’ Committee on Obstetric Practice. [18]

A recent literature review performed by Skowronski et al. (2009) found that TIV is warranted to protect women against influenza- related hospitalisation during the second half of normal pregnancy, but evidence is otherwise insufficient to recommend routine TIV as the standard of practice for all healthy women beginning in early pregnancy. [6] Similarly, another review looked at the evidence for the risks of influenza and the risks and benefits of seasonal influenza vaccination in pregnancy and concluded that data on influenza vaccine safety in pregnancy is inadequate. [19] However, based on the available literature, there was no evidence of serious side effects in women or their infants, including no indication of harm from vaccination in the first trimester. [19]

We aim to review the literature published on the delivery and uptake of influenza vaccination during pregnancy and identify the reasons for low adherence to guidelines. The review will increase our understanding of how the use of the influenza vaccination is perceived by health care providers and the pregnant women.

Evidence of health care provider’s attitude, knowledge and opinions

Several published studies have revealed data supporting deficits in the knowledge of health care providers regarding the significance of the vaccine and the national guidelines, hence suggesting a low rate of vaccine recommendation and uptake by pregnant women. [20] A research project in 2006 performed a cross-sectional study of the knowledge and attitudes towards the influenza vaccination in pregnancy amongst all levels of health care workers (HCW’s) working at the Department for Health of Women and Children at University of Milan, Italy. [20] The strength of this study was that it included 740 HCWs representing 48.4% working in obstetrics/gynaecology, 17.6% in neonatology and 34% in paediatrics, of whom 282 (38.1%) were physicians, 319 (43.1%) nurses, and 139 (18.8%) paramedics (health aides/healthcare assistants). The respondents were given a pilot-tested questionnaire about their perception of the seriousness of influenza, their general knowledge of influenza recommendations and preventive measures, and their personal use of influenza vaccination; which was to be self-completed in 20 mins in an isolated room. Descriptive analysis of the 707 (95.6%) HCWs that completed the questionnaire revealed that the majority (83.6%) of HCW’s in obstetrics/gynaecology never recommended the influenza vaccination to healthy pregnant women. Esposito et al. (2007) highlighted that only a small number of nurses and paramedics, from each speciality, regarded influenza as serious in comparison to the physicians. [20] Another study investigating practices of the Midwives found that only 37% believed that influenza vaccine is effective and 22% believed that the vaccine was a greater risk than influenza. [21] The results from these studies clearly indicate deficiencies in the general knowledge of influenza and its prevention amongst health care staff.

In contrast, a study by Wu et al. (2006) suggested unusually high vaccination uptake rate of the fellows from the American College of Obstetricians and Gynaecologists (ACOG) who live and practice in Nashville, Tennessee. [22] The survey focussed on physician knowledge, practices, and opinions regarding influenza vaccination of pregnant women. Results revealed that 89% of practitioners responded that they routinely recommend the vaccine to pregnant women and 73% actually administered the vaccination to pregnant and postpartum women. [21] Sixty-two percent responded that the earliest administration of the vaccine should be the second trimester, while 32% reported that it should be offered in the first trimester. Interestingly, 6% believed that it should not be delivered at all during the pregnancy. Despite the national recommendation to administer the vaccination routinely to all pregnant women, [4] more than half of the obstetricians preferred to withhold it until second trimester due to concerns regarding vaccine safety, association with spontaneous abortion and possibility of disruption in embryogenesis. [22] Despite the high uptake rate identified by the respondents, there are a few major limitations in this study. First, the researchers excluded the family physicians and midwives practicing obstetrics in their survey, which prevents a true representation of the sample population. Second, the vaccination rates were identified by the practitioners and not validated, which increases the likelihood of personal bias by the practitioners.

It is evident that HCWs attending to pregnant women and children have limited and frequently incorrect beliefs concerning influenza and its prevention. [20,23] A recent study by Tong et al. (2008) demonstrated that only 40% of the health care providers at the three hospitals studied in Toronto were aware of the high-risk status of pregnant women and only 65% were aware of the NACI recommendations. [23] Furthermore, obstetricians were less likely than family physicians to indicate that it was their responsibility to discuss, recommend, or provide influenza vaccination. [23] Tong et al. (2008) also demonstrated that high levels of provider knowledge about influenza and maternal vaccination, positive attitudes towards influenza vaccination, increased age, being a family physician, and having been vaccinated against influenza, were associated with recommending influenza vaccine to pregnant women. [23] This data is also supported by Wu et al. and Espostio et al.

In 2001, Silverman et al. (2001) concluded that physicians were more likely to recommend vaccine if they were aware of current ‘Centers for Disease Prevention and Control’ guidelines, gave vaccinations in their offices and had been vaccinated against influenza themselves. [24] Similarly, Lee et al. (2005) showed that midwives who received the immunisation themselves and firmly believed in its benefits, were more likely to offer it to pregnant women. [21] Wallis et al. (2006) conducted a multisite interventional study involving educational sessions with the physicians and the use of “Think Flu Vaccine” notes on active obstetric charts, to illustrate a fifteen fold increase in the rate of influenza vaccinations in pregnancy. [25] This study also demonstrated that increase in uptake was greater in family practices versus obstetric practices, and furthermore increased in small practices as opposed to large practices.

Overall, the literature here is derived mostly from American and Canadian studies as there is no data available for Australia. Existing data suggest that there is a significant lack of understanding regarding influenza vaccine safety, benefits and recommendations amongst the HCW’s. [20-27] These factors may lead to wrong assumptions and infrequent vaccine delivery.

Barriers in delivering the influenza vaccinations to pregnant women

Aside from the gaps in the health care provider’s understanding of vaccine safety and national guidelines, several other barriers in delivering the influenza vaccine to pregnant women have been identified. A study published in 2009, based on CDC analysis of data from the Pregnancy Risk Assessment and Monitoring System from Georgia and Rhode Island over the period of 2004-2007, showed that the most common reasons for not receiving the vaccination were, “I don’t normally get the flu vaccination” (69.4%), and “my physician did not mention anything about a flu vaccine during my pregnancy” (44.5%). [28] Lack of maternal knowledge about the benefits of the influenza vaccination has also been demonstrated by Yudin et al. (2009), who conducted a cross-sectional in hospital survey of 100 postpartum women during the influenza season in downtown Toronto. [29] This study concluded that 90% of women incorrectly believed that pregnant women have the same risk of complications as non-pregnant women and 80% incorrectly believed that the vaccine may cause birth defects. [29]. Another study highlighted that 48% of physician listed patient refusal as a barrier for administering the vaccine. [22] These results were supported by Wallis et al. (2006), which focused on using simple interventions such as chart reminders to surmount the gaps in knowledge of women. [25] ‘Missed opportunities’ by obstetricians and family physicians to offer the vaccination have been suggested as a major obstacle in the delivery of the influenza vaccination during pregnancy. [14,23,25,28]

During influenza season, hospitalized pregnant women with respiratory illness had significantly longer lengths of stay and higher odds of delivery complications than hospitalized pregnant women without respiratory illness. [5] In some countries cost-burden of the vaccine to women is another major barrier that contributes to lower vaccination rates among pregnant women. [22] This is not an issue in Australia where the vaccination is free for all pregnant women. Provision of free vaccination to all pregnant women is likely to have a significant advantage when considering the cost-burden of influenza on the health-care sector. However, the cost-burden on the patient can be viewed as lack of access, as reported by Shavell et al. (2012) As such patients that lacked insurance and transportation were less likely to receive the vaccine. [30]

This is supported by several studies that have shown that the vaccine is comparatively cost-effective when considering the financial burden of influenza related morbidity. [31] A 2006 study based on decision analysis modelling revealed that vaccination rate of 100% in pregnant women would save approximately 50 dollars per woman, resulting in a net gain of approximately 45 quality-adjusted hours relative to providing supportive care alone in the pregnant population. [32] Beigi et al. (2009) demonstrated that maternal influenza vaccination using either the single- or 2-dose strategy is a cost-effective approach when influenza prevalence is 7.5% and influenza-attributable mortality is 1.05%. [32] As the prevalence of influenza and/or the severity of the outbreak increases the incremental value of vaccination also increases. [32] Moreover, a study in 2006 has proven the cost-effectiveness to the health sector of the single dose influenza vaccination for influenza like illness. [31] Therefore, patient education about the relative cost- effectiveness of the vaccine and adequate reimbursement by the government is required to alleviate this barrier in other nations but not in Australia where the vaccination is free for all pregnant women.

Lack of vaccine storage facilities in physician offices is an important barrier preventing the recommendation and uptake of the vaccine by pregnant women. [23,33] A recent study monitoring the immunisation practices amongst practicing obstetricians found that less than 30% store influenza vaccine in their office. [18] One study showed acceptance rates of influenza vaccine of 71% of 448 eligible pregnant women who were offered the influenza vaccine at routine prenatal visit due to the availability of storage facilities at the practice, suggesting that the uptake of vaccination can be increased by simply overcoming the logistical and organisational barriers such as vaccine storage, inadequate reimbursement and patient education. [34]

Conclusion

From the limited data available, it is clear that there are is a variable level of knowledge of influenza and its prevention amongst HCWs. There is also and a general lack of awareness of the national guidelines in their countries. However, there is no literature for Australia to compare with other nations. There is some debate regarding the trimester in which the vaccine should be administered. There is further lack of clarity in terms of who is responsible for the discussion and delivery of the vaccine – the general practitioner or the obstetrician. These factors contribute to a lack of discussion of vaccine use and amplify the amount of ‘missed opportunities.’

Lack of maternal knowledge about the safety of the vaccine and its benefits is also a barrier that must be overcome by the HCW through facilitating an effective discussion about the vaccine. Since the vaccine has been rendered free in Australia, cost should not prevent vaccination. Regular supply and storage of vaccines especially in remote towns of Australia is likely to be a logistical challenge.

There is limited Australian literature exploring the uptake of influenza vaccine in pregnancy and the contributing factors such as the knowledge, attitude and opinion of HCWs, maternal knowledge of the vaccine and logistical barriers. A reasonable first step would be to determine the rates of uptake and prevalence of influenza vaccination in antenatal women in Australia.

Conflict of interest

None declared.

Correspondence

S Khosla: surabhi.khosla@my.jcu.edu.au

Cannabis is a promising therapeutic agent, which may be particularly beneficial in providing adequate analgesia to patients with neuropathic pain intractable to typical pharmacotherapy. Cannabinoids are the lipid-soluble compounds that mediate the analgesic effects associated with cannabis by interacting with the endogenous cannabinoid receptors CB1 and CB2, which are distributed along neurons associated with pain transmission. From the 60 different cannabinoids that can be found in cannabis plants, delta-9 tetrahydrocannabinol (THC) and cannabidiol are the most important in regards to analgesic properties. Whilst cannabinoids are effective in providing diminished pain responses, their therapeutic use is limited due to psychotropic side effects via interaction with CB1, which may lead to cannabis dependence. Cannabinoid ligands also interact with glycine receptors, selectively to CB2 receptors, and act synergistically with opioids and non-steroidal anti-inflammatory drugs (NSAIDs) to attenuate pain signals. This may be of therapeutic potential due to the lack of psychotropic effects produced. Clinical trials of cannabinoids in neuropathic pain have shown efficacy in providing analgesia; however, the small number of participants involved in these trials has greatly limited their significance. Although the medicinal use of cannabis is legal in Canada and some parts of the United States, its use as a therapeutic agent in Australia is not permitted. This paper will review the role cannabinoids play in providing analgesia, the pharmacokinetics associated with various routes of administration and dependence issues that may arise from its use.

Introduction

Compounds in plants have been found to be beneficial, and now contribute to many of the world’s modern medicines. Delta-9- tetrahydrocannibinol (THC), the main psychoactive cannabinoid derived from cannabis plants, mediates its analgesic effects by acting at both the central and peripheral cannabinoid receptors.[1] The analgesic properties of cannabis were first observed by Ernest Dixon in 1899, who discovered that dogs failed to react to pin pricks following the inhalation of cannabis smoke.[2] Since that time, there has been extensive research into the analgesic properties of cannabis, including whole plant and synthetic cannabinoid studies. [3-5]

Although the use of medicinal cannabis is legal in Canada and parts of the United States, every Australian jurisdiction currently prohibits its use.[6] Despite this, Australians lead the world in the illegal use of cannabis for both medicinal and recreational reasons. [7]

Although the analgesic properties of cannabis could be beneficial in treating neuropathic pain, the use of cannabis in Australia is a controversial, widely debated subject. The issue of dependence to cannabis arising from medicinal cannabis use is of concern to both medical and legal authorities. This review aims to discuss the pharmacology of cannabinoids as it relates to analgesia, and also the dependence issues that may arise from the use of cannabis.

Medicinal cannabis can be of particular benefit in the treatment of neuropathic pain that is intractable to the typical agents used, such as tricyclic antidepressants, anticonvulsants and opioids. [3,8] Neuropathic pain is a disease affecting the somatosensory nervous system which thereby causes pain that is unrelated to peripheral tissue injury. Treatment options are limited. The prevalence of chronic pain in Australia has been estimated at 20% of the population, [9] with neuropathic pain estimated to affect up to 7% of the population. [10]

The role of cannabinoids in analgesia

Active compounds found in cannabis

Cannabis contains over 60 cannabinoids, with THC being the quintessential mediator of analgesia and the only psychoactive constituent found in cannabis plants. [11] Another cannabinoid, cannabidiol, also has analgesic properties; however, instead of interacting with cannabinoid receptors, its analgesic properties are attributed to inhibition of anandamide degradation. [11] Anandamide is the most abundant endogenous cannabinoid in the CNS and acts as an agonist at cannabinoid receptors. By inhibiting the breakdown of anandamide, its time in the synapse is prolonged and its analgesic effects are perpetuated.

Cannabinoid and Vanilloid receptors

Distributed throughout the nociceptive pathway, cannabinoid receptors are a potential target for the administration of exogenous cannabinoids to suppress pain. Two known types of cannabinoid receptors, CB1 and CB2, are involved in pain transmission. [12] The CB1 cannabinoid receptor is highly expressed in the CNS as well as in peripheral tissues, and is responsible for the psychotropic effects produced by cannabis. There is debate regarding the location of the CB2 cannabinoid receptor, previously found to be largely distributed in peripheral immune cells. [12-13] Recent studies, however, suggest that CB2 receptors may also be found on neurons. [12-13] The CB2 metabotropic G-protein coupled receptors are negatively coupled to adenylate cyclase and positively coupled to mitogen-activated protein kinase. [14] The cannabinoid receptors are also coupled to pre-synaptic voltage-gated calcium channel inhibition and inward- rectifying potassium channel activation, thus depressing neuronal excitability, eliciting an inhibitory effect on neurotransmitter release and subsequently decreasing pain transmission. [14]

Certain cannabinoids have targets other than cannabinoid receptors through which they mediate their analgesic properties. Cannabidiol can act at vanilloid receptors, where capsacsin is active, to produce analgesia. [15] Recent studies have found that the actions of administered cannabinoids in mice have a synergestic effect to the response of glycine, an inhibitory neurotransmitter that may contribute to its analgesic effects. Analgesia was absent in mice that lacked glycine receptors, but not in those lacking cannabinoid receptors, thus indicating an important role of glycine in the analgesic affect of cannabis. [16] Throughout this study, modifications were made to the compound to enhance binding to glycine receptors and diminish binding to cannabinoid receptors, which may be of therapeutic potential to achieve analgesia without psychotropic side effects. [16]

Mechanism of action in producing analgesia and side effects

Cannabinoid receptors also play an important role in the descending inhibitory pathways via the midbrain periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM). [17] Pain signals are conveyed via primary afferent nociceptive fibres to the brain via ascending pain pathways that synapse on the dorsal horn of the spinal cord. The descending inhibitory pathway modulates pain transmission in the spinal cord and medullary dorsal horn via the PAG and RVM before noxious stimuli reaches a supraspinal level and is therefore interpreted as pain. [17] Cannabinoids activate the descending inhibitory pathway via gamma-aminobutyric acid (GABA)-mediated disinhibition, thus decreasing GABAergic inhibition and enhancing impulses responsible for the inhibition of pain; this is similar to opioid-mediated analgesia. [17]

Cannabinoid receptors, in particular CB1, are distributed throughout the cortex, hippocampus, amygdala, basal ganglia outflow tracts and cerebellum, which corresponds to the capacity of cannabis to produce motor and cognitive impairment. [18] These deleterious side effects limit their therapeutic use as an analgesic. Since ligands binding to CB1 receptors are responsible for mediating the psychotropic effects of cannabis, studies have been undertaken on the effectiveness of CB2 agonists; they were found to attenuate neuropathic pain without experiencing CB1-mediated CNS side effects. The discovery of a suitable CB2 agonist may be of therapeutic potential. [19]

Synergism with commonly used analgesics

Cannabinoids are also important in acting synergistically with non- steroidal anti-inflammatory drugs (NSAIDs) and opioids to produce analgesia; cannabis could thus be of benefit as an adjuvant to typical analgesics. [20] A major central target of NSAIDs and opioids is the descending inhibitory pathway. [20] The analgesia produced by NSAIDs through its action on the descending inhibitory pathway requires simultaneous activation of the CB1 cannabinoid receptor. In the presence of an opioid antagonist, cannabinoids are still effective analgesics. Whilst cannabinoids do not act via opioid receptors, cannabinoids and opioids show synergistic activity. [20] On the other hand, Telleria-Diaz et al. reported that the analgesic effects of non- opioid analgesics, primarily indomethacin, in the spinal cord can be prevented by a CB1 receptor antagonist, thus highlighting synergism between the two agents. [21] Although no controlled studies in pain management have used cannabinoids with opioids, anecdotal evidence suggest synergistic benefits in analgesia, particularly in patients with neuropathic pain. [20] Whilst the interaction between opioids, NSAIDs and cannabinoids is poorly understood, numerous studies do suggest that they act in a synergistic manner in the PAG and RVM via GABA- mediated disinhibition to enhance descending flow of impulses to inhibit pain transmission. [20]

Route of Administration

Clinical trials of cannabis as an analgesic in neuropathic pain have shown cannabis to reduce the intensity of pain. [5,22] The most common administration of medicinal cannabis is through inhalation via smoking. Two randomised clinical trials assessing smoked cannabis showed that patients with HIV-associated neuropathic pain achieved significantly reduced pain intensity (34% and 46%) compared to placebo (17% and18% respectively). [5,22] One of the studies was composed of participants whose pain was intractable to first-line analgesics used in neuropathic pain, such as tricyclic antidepressants and anticonvulsants. [22] The numbers needed to treat (NNT=3.5) were comparable to agents already in use (gabapentin: NNT=3.8 and lamotrigine: NNT=5.4). [22] All of the studies undertaken on smoked cannabis have been short-term studies and do not address long- term risks of cannabis smoking. An important benefit associated with smoking cannabis is that the pharmacokinetic profile is superior to orally ingested cannabinoids. [23]After smoking one cannabis cigarette, peak plasma levels of THC are reached within 3-10 minutes and due to its lipid solubility, levels quickly decrease as THC is rapidly distributed throughout the tissues. [23] While the bioavailability of THC when inhaled via smoke is much higher than oral preparations, due to first pass metabolism, there are obvious harmful affects associated with smoking which warranted the study of using other means of inhalation such as vapourisation. In medicinal cannabis therapy, vapourisation may be less harmful than smoking as the cannabis is heated below the point of combustion where carcinogens are formed. [24] A recent study found that the transition from smoking to vapourising in cannabis smokers improved lung function measurements and, following the study, participants refused to participate in a reverse design in which they would return to smoking. [24]

Studies undertaken on the efficacy of oro-mucosal cannabinoid preparations (Sativex) showed a 30% reduction in pain as opposed to placebo; the NNT was 8.6.[4] Studies comparing oral cannabinoid preparations (Nabilone) to dihydrocodeine in neuropathic pain found that dihydrocodeine was a more effective analgesic. [25] The effects of THC from ingested cannabinoids lasted for 4-12 hours with a peak plasma concentration at 2-3 hours. [26] The effects of oral cannabinoids was variable due to first pass metabolism where significant amounts of cannabinoids are metabolized by cytochrome P450 mixed-function oxidases, mainly CYP 2C9. [26] First pass metabolism is very high and bioavailability of THC is only 6% for ingested cannabis, as opposed to 20% for inhaled cannabis. [26] The elimination of cannabinoids occurs via the faeces (65%) and urine (25%), with a clinical study showing that after five days 90% of the total dose was excreted. [26]

The issue of cannabis dependence

One of the barriers to the use of medicinal cannabis is the controversy regarding cannabis dependence and the adverse effects associated with chronic use. Cannabis dependence is a highly controversial but important topic, as dependence may increase the risk of adverse effects associated with chronic use. [27] Adverse effects resulting from long-term use of cannabis include short term memory impairment, mental health problems and, if smoked, respiratory diseases. [28] Some authors report that cannabis dependence and subsequent adverse negative effects upon cessation are only observed in non- medical cannabis users, other authors report that dependence is an issue for all cannabis users, whether its use is for medicinal purposes or not. An Australian study assessing cannabis use and dependence found that one in 50 Australians had a DSM-IV cannabis use disorder, predominately cannabis dependence. [27] They also found that cannabis dependence was the third most common life-time substance dependence diagnosis following tobacco and alcohol dependence. [27] Cannabis dependence can develop; however, the risk factors for dependence come predominantly from studies that involve recreational users, as opposed to medicinal users under medical supervision. [29]

A diagnosis of cannabis dependence, according to DSM-IV, is made when three of the following seven criteria are met within the last 12 months: tolerance; withdrawal symptoms; cannabis used in larger amounts or for a longer period than intended; persistent desire or unsuccessful efforts to reduce or cease use; a disproportionate amount of time spent obtaining, using and recovering from use; social, recreational or occupational activities were reduced or given up due to cannabis use; and use continued despite knowledge of physical or psychological problems induced by cannabis. [29] Unfortunately, understanding of cannabis dependence arising from medicinal use is limited due to the lack of studies surrounding cannabis dependence in the context of medicinal use. Behavioural therapies may be of use; however, their efficacy is variable. [30] A recent clinical trial indicated that orally-administered THC was effective in alleviating cannabis withdrawals, which is analogous to other well-established agonist therapies including nicotine replacement and methadone. [30]

The pharmacokinetic profiles also affect cannabis dependence. Studies suggest that the risk of dependence seems to be marginally greater with the oral use of isolated THC than with the oral use of combined THC-cannabidiol. [31] This is important because hundreds of cannabinoids can be found in whole cannabis plants, and cannabidiol may counteract some of the adverse effects of THC; however, more studies are required to support this claim. [31]

The risk of cannabis dependence in the context of long term and supervised medical use is not known. [31] However, some authors believe that the pharmacokinetic profiles of preparations used for medicinal purposes differ from those used for recreational reasons, and therefore causalities in terms of dependence and chronic adverse effects between the two differ greatly. [32]

Conclusion

Cannabis appears to be an effective analgesic and provides an alternative to analgesic pharmacotherapies currently in use for the treatment of neuropathic pain. Cannabis may be of particular use in neuropathic pain that is intractable to other pharmacotherapy. The issue of dependence and adverse side effects including short term memory impairment, mental health problems and if smoked, respiratory diseases arising from medicinal cannabis use is a highly debated topic and more research needs to be undertaken. The ability of cannabinoids to modulate pain transmission by enhancing the activity of descending inhibitory pathways and acting as a synergist to opioids and NSAIDs is important as it may decrease the therapeutic doses of opioids and NSAIDs required, thus decreasing the likelihood of side effects. The possibility of a cannabinoid-derived compound with analgesic properties free of psychotropic effects is quite appealing, and its discovery could potentially lead to a less controversial and more suitable analgesic in the future.

Conflict of interest

None declared.

Correspondence

S Sargent: stephaniesargent@mail.com

Depression is one of the most common health problems addressed by general practitioners in Australia. It is well known that biological, psychosocial and environmental factors play a role in the aetiology of depression. Research into the possible biological mechanisms of depression has identified interleukin-6 (IL-6) as a potential biological correlate of depressive behaviour, with proposed contributions to the aetiology and pathogenesis of depression. Interleukin-6 is a key proinflammatory cytokine involved in the acute phase of the immune response and a potent activator of the hypothalamic-pitutary-adrenal axis. Patients with depression have higher than average concentrations of IL-6 compared to non- depressed controls, and a dose-response correlation may exist between circulating IL-6 concentration and the degree of depressive symptoms. Based on these insights the ‘cytokine theory of depression’ proposes that proinflammatory cytokines, such as IL-6, act as neuromodulators and may mediate some of the behavioural and neurochemical features of depression. Longitudinal and case- control studies across a wide variety of patient cohorts, disease states and clinical settings provide evidence for a bidirectional relationship between IL-6 and depression. Thus IL-6 represents a potential biological intermediary and therapeutic target for the treatment of depression. Recognition of the strong biological contribution to the aetiology and pathogenesis of depression may help doctors to identify individuals at risk and implement appropriate measures, which could improve the patient’s quality of life and reduce disease burden.

Introduction

Our understanding of the immune system has grown exponentially within the last century, and more questions are raised with each new development. Over the past few decades research has emerged to suggest that the immune system may be responsible for more than just fighting everyday pathogens. The term ‘psychoneuroimmunology’ was first coined by Dr Robert Ader and his colleagues in 1975 as a conceptual framework to encompass the emerging interactions between the immune system, the nervous system, and psychological functioning. Cytokines have since been found to be important mediators of this relationship. [1] There is considerable research that supports the hypothesis of proinflammatory cytokines, in particular interleukin-6 (IL-6), in playing a key role in the aetiology and pathophysiology of depression. [1-5] While both positive and negative results have been reported in individual studies, a recent meta-analysis supports the association between depression and circulating IL-6 concentration. [6] This review will explore the impact of depression in Australia, the role of IL-6 and the proposed links to depression and clinical implications of these findings.

Depression in Australia and its diagnosis

Depression belongs to a group of affective disorders and is one of the most prevalent mental illnesses in Australia. [7] It contributes to one of the highest disease burdens in Australia, closely following cancers and cardiovascular diseases. [7] Most of the burden of mental illness, measured as disability adjusted life years (DALYs), is due to years of life lost through disability (YLD) as opposed to years of life lost to death (YLL). This makes mental disorders the leading contributor (23%) to the non-fatal burden of disease in Australia. [7] Specific populations, including patients with chronic disease, such as diabetes, cancer, cardiovascular disease, and end-stage kidney disease, [1,3,4,10] are particularly vulnerable to this form of mental illness.[8, 9] The accurate diagnosis of depression in these patients can be difficult due to the overlapping of symptoms inherent to the disease or treatment and the diagnostic criteria for major depression. [10-12] Nevertheless, accurate diagnosis and treatment of depression is essential and can result in real gains in quality of life for patients with otherwise incurable and progressive disease. [7] Recognising the high prevalence and potential biological underpinnings of depression in patients with chronic disease is an important step in deciding upon appropriate diagnosis and treatment strategies.

Role of IL-6 in the body

Cytokines are intercellular signalling polypeptides produced by activated cells of the immune system. Their main function is to coordinate immune responses; however, they also play a key role in providing information regarding immune activity to the brain and neuroendocrine system. [13] Interleukin-6 is a proinflammatory cytokine primarily secreted by macrophages in response to pathogens. [14] Along with interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-α), IL-6 plays a major role in fever induction and initiation of the acute-phase response. [14] The latter response involves a shi

Introduction

The most recent epidemiological publication on the worldwide burden of cervical cancer has reported that cervical cancer (0.53 million cases) was the third most common female cancer reported in 2008 after breast (1.38 million cases) and colorectal cancer (0.57 million cases). [1] Cervical cancer is the leading source of cancer-related death among women in Africa, Central America, South-Central Asia and Melanesia, indicating that it remains a major public health problem in spite of effective screening methods and vaccine availability. [1]

The age-standardised incidence of cervical cancer in Australian women (20-69 years) has decreased by approximately 50% from 1991 (the year the National Cervical Screening Program was introduced) to 2006 (Figure 1). [2,3] Despite this drop, the Australian Institute of Health and Welfare estimated an increase in cervical cancer incidence and mortality for 2010 by 1.5% and 9.6 % respectively. [3]

Human papillomavirus (HPV) is required but not sufficient to cause invasive cervical cancer (ICC). [4-6] Not all women with a HPV infection progress to develop ICC. This implies the existence of cofactors in the pathogenesis of ICC such as smoking, sexually transmitted infections, age at first intercourse and number of lifetime sexual partners. [7] Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection (STI) and it has been associated with the development of ICC in many case-controlled and population based studies. [8-11] However, a clear cause-and effect relationship has not been elucidated between CT infection, HPV persistence and progression to ICC as an end stage. This article aims to review the literature for evidence that CT acts as a cofactor in the development of ICC and HPV establishment. The understanding of CT as a risk factor for ICC is crucial as it is amenable to prevention.

Aim: To review the literature to determine if an infection with Chlamydia trachomatis (CT) acts as a confounding factor in the pathogenesis of invasive cervical cancer (ICC) in women. Methods: Web-based Medline and the Australian Institute of Health and Welfare (AIHW) search for key terms: cervical cancer (including neoplasia, malignancy and carcinoma), chlamydia, human papillomavirus (HPV) and immunology. The search was restricted to English language publications on ICC (both squamous and adenocarcinoma) and cervical intraepithelial neoplasia (CIN) between 1990-2010. Results: HPV is essential but not sufficient to cause ICC. Past and current infection with CT is associated with squamous cell carcinoma of the cervix of HPV-positive women. CT infection induces both protective and pathologic immune responses in the host that depend on the balance between Type-1 helper cells versus Type-2 helper cell-mediated immunity. CT most likely behaves as a cervical cancer cofactor by 1) invading the host immune system and 2) enhancing chronic inflammation. These factors increase the susceptibility of a subsequent HPV infection and build HPV persistence in the host. Conclusion: Prophylaxis against CT is significant in reducing the incidence of ICC in HPVposi tive women. GPs should be raising awareness of the association between CT and ICC in their patients.

Evidence for the role of HPV in the aetiology and pathogenesis of cervical cancer

HPV is a species-specific, non-enveloped, double stranded DNA virus that infects squamous epithelia and consists of the major protein L1 and the minor capsid protein L2. More than 130 HPV types have been classified based on their genotype and HPV 16 (50-70% of cases) and HPV 18 (7-20% cases) are the most important players in the aetiology of cervical cancer. [6,12] Genital HPV transmission is usually spread via skin-to-skin contact during sexual intercourse but does not require vaginal or anal penetration, which implies that condoms only offer some protection against CIN and ICC. [6] The risk factors for contracting HPV infection are early age at first sexual activity, multiple sexual partners, early age at first delivery, increased number of pregnancies, smoking, immunosuppression (for example, human immunodeficiency virus or medication), and long-term oral contraceptive use. Social customs in endemic regions such as child marriages, polygamy and high parity use may also increase the likelihood of contracting HPV. [13] More than 80% of HPV infections are cleared by the host’s cellular immune response, which starts about three months from the inoculation of virus. HPV can be latent for 2-12 months post-infection. [14]

Molecular Pathogenesis

HPV particles enter basal keratinocytes of mucosal epithelium via binding of virions to the basal membrane of disrupted epithelium. This is mediated via heparan surface proteoglycans (HSPGs) found in the extracellular matrix and cell surface of most cells. The virus is then internalised to establish an infection mainly via a clathrin-dependent endocytic mechanism. However, some HPV types may use alternative uptake pathways to enter cells, such as a caveolae-dependent route or the involvement of tetraspanin-enriched domains as a platform for viral uptake. [15] The virus replicates in nondividing cells that lack the necessary cellular DNA polymerases and replication factors. Therefore, HPV encodes proteins that reactivate cellular DNA synthesis in noncycling cells, inhibit apoptosis, and delay the differentiation of the infected keratinocyte, to allow viral DNA replication. [6] The integration of viral genome in the host DNA causes deregulation of E6 and E7 oncogenes of high-risk HPV (HPV 16 and 18) but not of low risk HPV (HPV 6 and 11). This results in the expression of E6 and E7 oncogenes throughout the epithelium resulting in aneuploidy and karotypic chromosomal abnormalities that accompany keratinocyte immortalisation. [5]

Natural History of HPV infection and cervical cancer

Low risk HPV infections are usually cleared by cellular immunity coupled with seroconversion and antibodies against major coat protein L1. [5,6,12] Infection with high-risk HPV is highly associated with the development of squamous cell and adenocarcinoma of the cervix, which is confounded by other factors such as smoking and STIs. [4,9,10] The progression of cervical cancer in response to HPV is schematically illustrated in Figure 2.

Chlamydia trachomatis and the immune response

CT is a true obligate intracellular pathogen and is the most common bacterial cause of STIs. It is associated with sexual risk-taking behaviour and leads to asymptomatic and therefore undiagnosed genital infections due to the slow growth cycle of CT. [16] A CT infection is targeted by innate immune cells, T cells and B cells. Protective immune responses control the infection whereas pathological responses lead to chronic inflammation that causes tissue damage. [17]

Innate immunity

The mucosal epithelium of the genital tract provides first line of host defence. If CT is successful in entering the mucosal epithelium, the innate immune system is activated through the recognition of pathogen-associated molecular patterns (PAMPs) such as the Toll-like receptors (TLRs). Although CT lipopolysaccharides can be recognised by TLR4, TLR2 is more crucial for signalling pro-inflammatory cytokine production. [18] This leads to the production of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, tumour necrosis factor-a (TNF-a) and granulocyte-macrophage colony-stimulating factor (GMCSF). [17] In addition, chemokines such as IL-8 can increase recruitment of innate-immunity cells such as macrophages, natural killer (NK) cells, dendritic cells (DCs) and neutrophils that in turn produce more proinflammatory cytokines to restrict CT growth. Infected epithelial cells release matrix metalloproteases (MMPs) that contribute to tissue proteolysis and remodelling. Neutrophils also release MMPs and elastases that contribute to tissue damage. NK cells produce interferon (IFN)–gamma that drives CD4 T cells toward the Th1-mediated immune response. The infected tissue is infi ltrated by a mixture of CD4, CD8, B cells, and plasma cells (PCs). [17,19,20] DCs are essential for processing and presenting CT antigens to T cells and therefore linking innate and adaptive immunity.

Adaptive Immunity

Both CD4 and CD8 cells contribute to control of CT infection. In 2000, Morrison et al. showed that B cell-deficient mice, depleted of CD4 cells, are unable to clear CT infection. [21] However, another study in 2005 showed that passive transfer of chlamydia-specific monoclonal antibodies into B-cell deficient and CD4 depleted cells restored the ability of these mice to control a secondary CT infection. [22] This indicates a strong synergy between CD4 and B cells in the adaptive immune response to CT. B cells produce CT-specific antibodies to combat the pathogens. In contrast, CD8 cells produce IL-4, IL-5 and IL- 13 that do not appear to protect against chlamydia infection and may even indirectly enhance chlamydia load by inhibiting the protective CD4 response. [23] A similar observation was made by Agrawal et al. who examined cervical lymphocyte cytokine responses of 255 CT antibody–positive women with or without fertility disorders (infertility and multiple spontaneous abortions) and of healthy control women negative for CT serum IgM or IgG. [20] The study revealed a significant increase in CD4 cells in the cervical mucosa of fertile women, compared with those with fertility disorders and with negative control women. There was a very small increase in CD8 cells in cervical mucosa of CT infected women in both groups. The results showed that cervical cells from the women with fertility disorders secreted higher levels of IL- 1b, IL-6, IL-8, and IL-10 in response to CT; whereas, cervical cells from antibody-positive fertile women secreted significantly higher levels of IFN-gamma and IL-12. This suggests that a skewed immune response toward Th1 prevalence protects against chronic infection. [20]

The pathologic response to CT can result in inflammatory damage within the upper reproductive tract due to either failed or weak Th1 action resulting in chronic infection or an exaggerated Th1 response. Alternatively, chronic infection can occur if Th2 response dominates Th1 immune response and result in autoimmunity and direct cell damage which in turn will enhance tissue inflammation. Inflammation also increases the expression of human heat shock protein (HSP), which induce production of IL-10 via autoantibodies leading to CT associated pathology such as tubal blockage and ectopic pregnancies. [24]

Evidence that Chlamydia trachomatis is a cofactor for cervical cancer

Whilst it has been established that HPV is a necessary factor in the development of cervical cancer, it is still unclear why the majority of women infected with HPV do not progress to ICC stage. Several studies in the last decade have focused on the role of STIs in the pathogenesis of ICC and discovered that CT infection is consistently associated with squamous cell ICC.

In 2000, Koskela et al. performed a large-scale case-controlled study within a cohort of 530,000 Nordic women to evaluate the role of CT in the development of ICC. [10] One-hundred and eighty-two women with ICC (diagnosed during a mean follow-up of five years after serum sampling) were identified via linking data files of three Nordic serum banks and the cancer registries of Finland, Norway and Sweden. Microimmunofl uorescence (MIF) was used to detect CT-specific IgGs and HPV16-, 18- and 33-specific IgG antibodies were determined by standard ELISAs. Serum antibodies to CT were associated with an increased risk for cervical squamous-cell carcinoma (HPV and smoking adjusted odds ratio (OR), 2.2; 95% confi dence interval (CI), 1.3–3.5). The association remained also after adjustment for smoking both in HPV16-seronegative and seropositive cases (OR, 3.0; 95% CI, 1.8–5.1; OR, 2.3, 95% CI, 0.8–7.0 respectively). This study provided sero-epidemiologic evidence that CT could cause squamous cell ICC. However the authors were unable to explain the biological association between CT and squamous cell ICC.

Many more studies emerged in 2002 to investigate this association between CT and ICC even further. Smith et al. performed a hospital case-controlled study of 499 ICC women from Brazil and 539 from Manila that revealed that CT seropositive women have a twofold increase in squamous ICC (OR, 2.1; 95% CI, 1.1-4.0) but not adenocarcinoma or adenosquamous ICC (OR, 0.8; 95% CI, 0.3-2.2). [8] Similarly, Wallin et al. conducted a population based prospective study of 118 women who developed cancer after having a normal pap smear (average of 5.6 years later). [25] Women were followed up for 26 years. PCR analysis for CT and HPV DNA showed that the relative risk for ICC associated with past CT, adjusted for concomitant HPV DNA positivity, was 17.1. They also concluded that the presence of CT and of HPV was not interrelated.

In contrast, another study examining the association between CT and HPV in women with cervical intraepithelial neoplasia (CIN) found that there is an increase in CT rate in HPV-positive women (29/49) as compared to HPV-negative women (10/80), (p<0.001). [26] However, no correlation between HPV and CT co-infection was found and the authors suggested that the increased CT infectivity rate in HPVposi tive women is presumably due to HPV-related factors, including modulation of the host’s immunity. In 2004, a case-controlled study of 1,238 ICC women and 1100 control women in 7 countries coordinated by the International Agency for Research on Cancer (IARC), France also supported the findings of previous studies. [7]

Strikingly, a very recent study in 2010 confirmed that there was no association between CT infection, as assessed by DNA or IgG, and risk of cervical premalignancy, after controlling for carcinogenic HPVposi tive status. [11] The authors have justified the difference in results from previous studies by criticising the retrospective nature of the IARC study, which meant that HPV and CT status at relevant times were not available. [7] However, other prospective studies have also identified the association between CT and ICC development. [9,25] Therefore, the results from this one study remain isolated from practically every other study that has found an association between CT and ICC in HPV infected women.

Consequently, it is evident that CT infection has a role in confounding squamous cell ICC in HPV infected women but it is not an independent    cause for ICC as previously suggested by Koskela et al. [10] Previous cause-and-eff ect association between CT and HPV are most likely from CT infection increasing the susceptibility to HPV. [9,11,27] The mechanisms by which CT can act as a confounder for ICC relate to CT induced inflammation (associated with metaplasia) and invasion of the host immune response, which increases susceptibility to HPV infection and enhances HPV persistence in the host. CT can directly degrade RFX-5 and USF-1 transcription factors that induce expression of MHC class I and MHC class II respectively. [17,28] This prevents recognition of both HPV and CT by CD4 and CD8 cells, thus preventing T-cell effector functions. CT can also suppress IFN-gamma-induced MHC class II expression by selective disruption of the IFN-gamma signalling pathways, hence evading host immunity. [28] Additionally, as discussed above, CT induces inflammation and metaplasia of infected cells, which predisposes them as target cells for HPV. CT infection may also increase access of HPV to the basal epithelium and increases HPV viral load. [16]

Conclusion

There is sufficient evidence to suggest that CT infection can act as a cofactor in squamous cell ICC development due to consistent positive correlations between CT infection and ICC in HPV positive women. CT invades the host immune response due to chronic inflammation and it is presumed that it prevents the clearance of HPV from the body, thereby increasing the likelihood of developing ICC. More studies are needed to establish the clear biological pathway linking CT to ICC to support the positive correlation found in epidemiological studies. An understanding of the significant role played by CT as a cofactor in ICC development should be exercised to maximise efforts in CT prophylaxis, starting at the primary health care level. Novel public health strategies must be devised to reduce CT transmission and raise awareness among women.

Conflicts of interest

None declared.

Correspondence

S Khosla: surkhosla@hotmail.com