Transient Exacerbation Of Pain Research Articles

Breakthrough pain among cancer patients at oncology units in Northern Ethiopia; a multi-center study.

Breakthrough cancer pain (BTCP) is a transient exacerbation of pain that affects the length of hospitalization and quality of life of patients. The objective of this study was to determine the prevalence and factors associated with BTCP among cancer patients at oncology units in Northern Ethiopia in 2022. A multi-center cross-sectional study was conducted from April to June 2022. After obtaining ethical approval, data were collected prospectively from 424 adult cancer patients admitted to oncology units. Breakthrough cancer pain was assessed by the numeric rating scale. Descriptive and binary logistic regression analyses were performed to determine the factors associated with BTCP. The strength of association was described in adjusted odds ratio (AOR) with 95% confidence intervals and variables with a P-value < 0.05 were considered to have a statistically significant association with BTCP. The prevalence of BTCP among cancer patients was 41.5%. The factors that were found to be associated with BTCP were colorectal cancer (AOR: 7.7, 95% CI: 1.8, 32.3), lung cancer (AOR: 6.9, 95% CI: 1.9, 26.0), metastasis (AOR: 9.3, 95% CI: 3.0, 29.1), mild background pain (AOR: 7.5, 95% CI: 2.5, 22.6), moderate background pain (AOR: 7.0, 95% CI: 2.2, 23.1), severe background pain (AOR: 7.1, 95% CI: 2.2, 22.8), no analgesics taken for background pain (AOR: 5.1, 95% CI: 2.8, 9.3) and uncontrolled background pain (AOR: 3.3, 95% CI: 1.8, 6.1). The prevalence of BTCP was high. Colorectal cancer, lung cancer, the presence of metastasis, the presence of background pain, not taking analgesics for background pain, and uncontrolled background pain were significantly associated with BTCP.

Opioid analgesics for nociceptive cancer pain: Acomprehensive review.

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.

Light-Induced Activation of a Specific Type-5 Metabotropic Glutamate Receptor Antagonist in the Ventrobasal Thalamus Causes Analgesia in a Mouse Model of Breakthrough Cancer Pain.

Breakthrough cancer pain (BTcP) refers to a sudden and transient exacerbation of pain, which develops in patients treated with opioid analgesics. Fast-onset analgesia is required for the treatment of BTcP. Light-activated drugs offer a novel potential strategy for the rapid control of pain without the typical adverse effects of systemic analgesic drugs. mGlu5 metabotropic glutamate receptor antagonists display potent analgesic activity, and light-induced activation of one of these compounds (JF-NP-26) in the thalamus was found to induce analgesia in models of inflammatory and neuropathic pain. We used an established mouse model of BTcP based on the injection of cancer cells into the femur, followed, 16 days later, by systemic administration of morphine. BTcP was induced by injection of endothelin-1 (ET-1) into the tumor, 20 min after morphine administration. Mice were implanted with optic fibers delivering light in the visible spectrum (405 nm) in the thalamus or prelimbic cortex to locally activate systemically injected JF-NP-26. Light delivery in the thalamus caused rapid and substantial analgesia, and this effect was specific because light delivery in the prelimbic cortex did not relieve BTcP. This finding lays the groundwork for the use of optopharmacology in the treatment of BTcP.

Second Signatory: Hindrance to Effective Breakthrough Pain Management?

Background: Breakthrough cancer pain is defined as a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. Fentanyl citrate sublingual Tablet (FST) is administered to control breakthrough pain (BTP) and a ‘top-up’ dose is administered in 15 minutes if the pain does not respond. However, Nursing &amp; Midwifery council (UK) recommends that for administration of controlled drugs (CD), a secondary signatory is required within secondary care. Aims: To establish that breakthrough analgesia is administered on an in-patient unit according to the guidance. Methods: Retrospective data was collected on patients at an adult Palliative care unit, requiring second dose of FST. Results and Analysis: Over a period of 3 months, 46 episodes of BTP requiring second dose of FST were recorded. Top-up dose was signed for at 15 minutes for only 13 (28.2%) episodes. Further 14 (30.4%) doses were signed for with 5 minutes delay (20 minutes in total from first dose). 19 (41.3%) doses were signed for after 20 minutes with a range of 25-50 minutes (10 – 35 minutes delay). Note that there will be a further delay in administering the dose. Conclusion: Majority of patients have BTP for less than 45 minutes. After reporting, it takes time to get the medication to patient. Second dose may get further delayed causing pain prolongation. This delay is due to finding second nurse to check medication. There are various solutions which could be employed to prevent this delay and to achieve effective BTP management.

Cultural adaptation and psychometric validation of the Portuguese breakthrough pain assessment tool with cancer patients.

Breakthrough cancer pain (BTcP) is a transient exacerbation of pain that occurs over persistent, stable, and adequately controlled cancer background pain. It is prevalent and bears severe consequences to patients' quality-of-life. The effective management of BTcP depends on fast and reliable (re)assessment. The Breakthrough pain Assessment Tool (BAT) is one of the most concise and reliable self-report instruments adapted to clinical contexts so far, showing goodpsychometric qualities in the United Kingdom, the Netherlands, and South Korea. As to promote the effective management of BTcP in Portuguese-speaking communities this study, first aimed to culturally adapt and validate the Portuguese version of the BAT (BAT-Pt). Second, and most importantly, it sought to provide novel evidence on its criterion validity by investigating its association with measures of psychological distress, which has not been yet investigated. The BAT was translated into European Portuguese, using the back-translation method, and culturally adapted. Its psychometric properties (factor structure, internal consistency, construct and criterion validity) were analyzed in a cross-sectional multicenter study, with a sample of 65 cancer patients (49.2% women) recruited from eight hospitals in mainland Portugal (a priori power analysis determined a minimum sample of 50). Health professionals collected patients' clinical information, assessed their functional disability (ECOG Performance Status) and the adequacy of pain control. In addition to the Portuguese version of the BAT (BAT_Pt), patients completed the Portuguese versions of the Brief Pain Inventory, the Hospital Anxiety and Depression Scale, a Distress Thermometer and answered questions about the adequacy of pain control. The BAT-Pt was very well accepted by experts and patients. As hypothesized, a Principal Axis Factor Analysis revealed two underlying factors accounting for 55.2% of the variance: (1) Pain Severity and Impact of BTcP and (2) Duration of BTcP and Medication Inefficacy. Two items (on episode frequency and medication efficacy) were analyzed separately given their lower/cross loadings. The BAT-Pt showed good internal consistency overall (α=0.79) and for each sub-scale, namely, Pain Severity and Impact of BTcP (n=5 items; α=0.86) and Duration of BTcP and Medication Inefficacy (n=2 items; rsb=0.62). The BAT-Pt showed good convergent validity, being moderately to strongly associated with overall pain severity and interference (0.46<r<0.77, p<0.001). It also showed good concurrent validity by being associated not only with physical outcomes- such as functional disability (r=0.40, p<0.001) and patient- and physician-determined adequacy of BTcP control (|0.25<rpb<0.63|, p s <0.05)- but also, with distress (0.33<r<0.46, p s <0.001), anxiety (0.28<r<0.44, p s <0.05) and depression (r=0.47, p<0.001). The BAT-Pt is a reliable and valid measure of breakthrough pain in Portuguese cancer patients and it is strongly associated to physical and psychological outcomes. This study confirms and extends the psychometric validation of the BAT to a new cultural context, promoting its diffusion and use by researchers and clinicians in Portuguese-speaking communities. The BAT-Pt may be an invaluable tool for daily clinical practice by tapping multiple aspects of BTcP experiences that are associated to patients' physical and psychological outcomes.

Observational study to analyse the opioid titration process in the treatment of breakthrough pain of cancer patients in clinical practice

Background: During the oncological disease, patients may suffer a special type of pain called breakthrough pain (BTP), defined as a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. Opioids are an essential part of BTP treatment, and its dosing adjustment should be performed irrespective of the basal dose of analgesia. However, in clinical practice it is unknown how opioids titration is completed. The context and purpose of the study: The objective of the study was to assess opioid titration process for the treatment of breakthrough pain (BTP) in cancer patients in usual clinical practice.

Transmucosal fentanyl administration: sublingual, buccal, nasal - all the same? Treatment of breakthrough cancer pain

Transient exacerbation of pain in cancer patients (breakthrough cancer pain, BTCP) despite adequately controlled background pain should be regarded as an independent disease and receive targeted treatment. The opioid of choice is fentanyl, a rapid onset and highly potent WHO category III analgesic. Fentanyl has a strong first pass effect when administered orally and resorbed enterally, however it is well suited for transmucosal administration, e.g. on the oral or nasal mucosa. Seven different preparations of rapid onset fentanyl for transmucosal administration via various administration pathways are currently available in Germany. The aim of this review article was to determine which patient can benefit most from which forms of administration. Since there are hardly any direct comparisons of administration forms among each other, meta-analyses and reviews were included in the assessment. Tablets with an applicator (lozenge), sublingual and buccal tablets, as well as a buccal film are available for the oral transmucosal administration of fentanyl; there is an aqueous fentanyl nasal spray and a pectin-rich nasal spray for nasal transmucosal administration. The individual preparations differ considerably with regard to their pharmacological (e.g. bioavailability, cmax and tmax) and patient-relevant parameters (e.g. onset of action, potency and duration of effect). Fentanyl nasal spray is superior to the other forms of administration in terms of rapid onset of action and clinically relevant pain reduction and can thus be recommended as a treatment option for rapidly evolving and/or spontaneously occurring breakthrough cancer pain.

Breakthrough Cancer Pain: A Systematic Review of Pharmacologic Management .

Breakthrough cancer pain (BtCP), defined as a transient exacerbation of pain that occurs in conjunction with well-controlled background pain, is a common and burdensome problem in patients with cancer. . The aim of this systematic review is to identify evidence-based pharmacologic modalities for adequate management of BtCP. . PubMed and CINAHL® databases were searched to identify literature regarding pharmacologic strategies for BtCP published from January 2006 to June 2016. These studies were then synthesized by the Oncology Nursing Society Putting Evidence Into Practice pain team. . Forty-four studies provide evidence for the use of opioids for the management of BtCP. Transmucosal immediate-release fentanyl (TIRF) was found to have the most evidence for BtCP. Five studies and guidelines also suggest that oral opioids (not including TIRF products) be dosed proportionally to baseline opioids at 10%-20% of the 24-hour, around-the-clock dose.

Breakthrough Cancer Pain

Breakthrough cancer pain is a transient exacerbation of pain that occurs despite relatively well controlled background pain with around-the-clock analgesia. It is highly p revalent in patients with cancer pain, with an overall prevalence of 70∼90%. Breakthrough cancer pain has several negative effects on quality of life, including a decrease in functional status and social relationship, and higher incidence of anxiety/depression. It also places a detrimental burden on their families, society, and the healthcare system. According to the pathogenic mechanism, breakthrough cancer pain is classified into two categories: idiopathic (or spontaneous) pain and incident pain. Episodes of breakthrough cancer pain have typical characteristics, including rapid onset (5∼10 min), severe intensity, and short duration (30∼60 min). However, there are some variations in timing and severity of pain among patients and episodes. Therefore, a thorough assessment of pain episodes is needed and management plan must be individualized to provide optimal treatment. Several immediate-release formulations such as oxycodone, morphine, and hydromorphone are widely used despite relatively slow onset of action. Recent studies have shown that transmucosal fentanyl preparations were effective for faster control of breakthrough pain. We hope to improve management of breakthrough cancer pain with more efficient analgesics in l ine with currently available evidence.

Breakthrough cancer pain: a comparison of surveys with European and Canadian patients

Breakthrough cancer pain is defined as a transient exacerbation of pain that occurs spontaneously or in response to a trigger, despite stable and controlled background pain. Breakthrough pain often causes significant functional impairments for patients and can decrease quality of life. The objective of the study was to determine differences between breakthrough cancer pain incidence and management in Canada and Europe. Data collected from previous studies of breakthrough cancer pain in Canada and Europe was compared. A standard survey with identical inclusion/exclusion criteria was utilized for both patient populations. Both groups of patients had a similar number and duration of breakthrough pain episodes, and similar pain intensity and pain interference with their daily activities. European patients reported better analgesic efficacy and satisfaction with management, and a greater percentage of European patients were prescribed a transmucosal fentanyl formulation (19.1 vs 2.9 %). More European patients (55 %) than Canadian patients (32.5 %) took their rescue medication every time they had a breakthrough pain episode. Breakthrough cancer pain in both Canadian and European patients greatly impacts their daily living, and both groups of patients had similar experiences with breakthrough cancer pain. Currently, this pain is not adequately managed for many patients. The role for new analgesic treatments in management of breakthrough cancer pain needs further study.

Single-dose fentanyl sublingual spray for breakthrough cancer pain

Breakthrough cancer pain (BTCP) is defined as a transient exacerbation of pain that arises in patients with otherwise controlled persistent pain. BTCP typically has a rapid onset and relatively short duration, but it causes a significant amount of physical and psychological distress for patients. Several rapid-onset fentanyl formulations have been introduced in the USA to replace traditional oral opioids for the treatment of BTCP: a transmucosal lozenge, a sublingual orally disintegrating tablet, a buccal tablet, a buccal soluble film, a pectin nasal spray and, the newest formulation to enter the market, a sublingual spray. This article reviews the six rapid-onset formulations of fentanyl approved in the USA for the management of BTCP with emphasis on describing the published literature on fentanyl sublingual spray. The different fentanyl formulations vary in pharmacokinetic properties and ease of use, but all have a rapid onset and a relatively short duration of analgesia. Fentanyl sublingual spray has demonstrated absorption within 5 minutes of administration, with fentanyl plasma concentrations increasing over the first 30 minutes and remaining elevated for 60–90 minutes in pharmacokinetic studies in healthy subjects. Fentanyl sublingual spray shows linear dose proportionality, and changes in the temperature or acidity of the oral cavity do not alter its pharmacokinetic properties. In patients with BTCP, statistically significant pain relief is measurable at 5 minutes after administration of fentanyl sublingual spray, when compared with placebo, with significant pain relief lasting at least 60 minutes after administration. Adverse events are typical of opioid treatment and are considered mild to moderate in intensity. In summary, fentanyl sublingual spray provides rapid onset of analgesia and is a tolerable and effective treatment for BTCP.

A survey of Canadian cancer patients’ perspectives on the characteristics and treatment of breakthrough pain

Breakthrough pain is defined as a transient exacerbation of pain that occurs spontaneously or in response to a trigger despite stable and controlled background pain. The purpose of this study was to explore Canadian patients' awareness of and experience with breakthrough pain in cancer (BTPc). Four Canadian cancer centers participated in a non-interventional survey recruiting cancer patients who experienced breakthrough pain. These patients were asked about their pain, its impact on functioning, current management and interest in new treatments of BTPc. Ninety-four Canadian cancer patients participated in this study, with 96% stating that cancer pain impacted their daily living with over half unable to go to work or shopping. Fifty percent of patients said that an episode of BTPc lasted greater than 60 minutes, with the pain score being on average 7.8/10, impacting normal work (7.2/10) and general activity (7.1/10). Only 35% of patients were very satisfied with the speed of relief of their medications. Those who did not take their breakthrough pain medication for every episode stated that was because the pain was not always severe (37%), or they were afraid of becoming tolerant (23%) or addicted (12%). Patients stated that the most important features of a new treatment for BTPc were the ability to relieve pain completely (47%), and quickly (43%). Patients expressed willingness to try transmucosal products (80%) or nasal products (59%). Breakthrough cancer pain in Canadian cancer patients greatly impacts their daily lives. There is room for improvement in the management of BTPc, and the majority of patients would be willing to try new treatments.

Fentanyl sublingual spray for breakthrough pain in cancer patients.

Breakthrough pain is a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. Typically, breakthrough pain has a fast onset and short duration, and a significant impact on patients’ quality of life. Normal-release oral opioids are the traditional pharmacological approach for patients who are receiving an around the clock opioid regimen; however, their onset and duration of action may not be suitable for treating many breakthrough pains. Efforts to provide nonparenteral opioid formulations that could provide more rapid, and more effective, relief of breakthrough pain have led to the development of transmucosal opioid formulations including fentanyl sublingual spray (FSLS). This is a formulation of fentanyl available in doses of 100, 200, 400, 600, and 800 μg strengths approved for the management of breakthrough pain in adult cancer patients already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. Published pharmacokinetic, efficacy, tolerability, and safety data suggest that FSLS has a valuable role to play in the symptomatic pharmacological management of breakthrough pain. The effective dose of FSLS is determined by titration according to the needs of the individual patient.

CT-guided transforaminal cervical and lumbar epidural injections

Transforaminal injections are widely used. Serious complications including strokes and paraplegia have been reported after transforaminal injections of corticosteroids, and the Afssaps (2011) has issued a warning about their use [1]. The needle must be positioned in the posterior aspect of foramen, and its correct placement validated by an injection of contrast product. It is preferable to choose cortivazol (Altim(®)) as the corticoid for injection. This procedure is simple, reproducible, and durably effective in 60 to 70% of cases. Complications and adverse effects are rare but potentially serious: allergies, blood pressure surge, vasovagal syncope, transient exacerbation of pain, infection, stroke, and paraplegia. The aim of this course is to stress the need for rigor -in the indication, the technical performance of the procedure, and the overall management of the patient.

Pharmacotherapy for Breakthrough Cancer Pain

Breakthrough pain (BTP) is a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. The principal pharmacological treatment of BTP is represented by the administration of opioids as needed. Oral opioids have traditionally been the only available drugs for BTP. However, the onset and duration of action of oral opioids such as morphine or oxycodone may not be suitable for treating many episodes of BTP that are of short onset and duration. Transmucosal administration of lipophilic substances has gained a growing popularity in recent years due to the rapid effect, clinically observable 10-15 minutes after drug administration, and the non-invasive form. Different technologies have been developed to provide fast pain relief with potent opioid drugs such fentanyl, delivered by non-invasive routes (rapid onset opioids, ROOs). All the studies performed with ROOs have recommended that these drugs should be administered to opioid-tolerant patients receiving doses of oral morphine equivalents of at least 60 mg. These preparations, including oral transmucosal fentanyl citrate, fentanyl buccal tablet, sublingual fentanyl, intranasal fentanyl spray, fentanyl-pectin nasal spray and fentanyl buccal soluble film have shown better efficacy than placebo or oral opioids. Long-term studies have confirmed their efficacy and safety.

Chinical diagnosis and therapy of breakthrough pain in cancer patients

Blackground Breakthrough pain (BTP) is a transient exacerbation of pain with moderate and severe intensity and has high incidence in patients with cancer. Breakthrough pain lacks a consensus international definition and diagnosis standard,and clinical treatment of which is subsequently inadequate. Therefore it is difficult to manage breakthrough pain in patients with cancer. Objective This article is to summed up the newest development about the diagnosis and treatment of breakthrough pain in order to provide the evidence for clinical management. Content The diagnosis of breakthrough pain includes definition,epidemiology, classification and evaluation. However, management of breakthrough pain involves pharmacological and nonpharmacological treatment. Trend The most common therapy of breakthrough pain is administration of short and quick analgesics. However, the ideal management of breakthrough pain may require a combination of pharmacological with nonpharmacological treatment strategies. Key words: Cancer; Breakthrough pain; Diagnosis; Management

Assessing the impact of breakthrough cancer pain

Breakthrough pain is a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger despite relative stable and adequately controlled background pain. Breakthrough pain is a common and distinct component of cancer pain and is typically of rapid onset, severe in intensity, and generally self-limiting with an average duration of 30-60minutes. Despite the self-limiting nature of breakthrough pain, it can place significant physical, psychological, and economic burdens on both patients and their carers. Patients with breakthrough pain are often less satisfied with their analgesic therapy, they have decreased functioning because of their pain, and may also experience social and psychosocial consequences, such as increased levels of anxiety and depression. Successful management of breakthrough pain is best achieved by a thorough assessment which includes determining the severity, pathophysiology, and aetiology of the pain and takes into account both background and breakthrough pains while considering whether the underlying disease, co-morbidities or precipitating events are amenable to interventions. The features of breakthrough pain and the challenges it presents to patients, their carers, and health professionals are illustrated with a case study.

Breakthrough Pain in Cancer Patients

Breakthrough pain is a transient exacerbation of pain that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. A typical episode of breakthrough pain has a fast onset and short duration, yet despite the self-limiting nature of each breakthrough pain, the repeated episodes can have a significant effect on patients’ quality of life. Normal-release oral opioids have been the mainstay pharmacological approach for patients who are receiving an around the clock opioid regimen, but the onset and duration of action of oral opioids such as morphine may not be suitable for treating many breakthrough pains. Efforts to provide non-parenteral opioid formulations that could provide more rapid, and more effective, relief of breakthrough pain have led to the development of transmucosal opioid formulations.

Dynamics of breakthrough pain vs. pharmacokinetics of oral morphine: implications for management

Dynamics of breakthrough pain vs. pharmacokinetics of oral morphine: implications for managementBreakthrough pain is a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. The onset of breakthrough pain is typically fast and the duration is usually relatively short, but despite the self-limiting nature of each breakthrough pain, the repeated episodes can have a significant impact on patients' quality of life. Effective management is therefore imperative and often involves the use of supplemental doses of medication known as 'rescue medication'. The ideal rescue medication should be efficacious, have a rapid onset of action, a relatively short duration of effect and minimal adverse effects. Normal-release oral opioids have been the mainstay approach for patients who are receiving around the clock opioid regimen, but the onset and duration of action of oral opioids such as morphine may not be suitable for treating many breakthrough pains.

Impact and management of breakthrough pain in cancer

To outline the impact of breakthrough pain, the evidence for the current management and new treatment options that are becoming available. Breakthrough pain is a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. Despite its self-limiting nature, breakthrough pain can place significant physical, psychological, and economic burdens on both patients and their carers. The successful management breakthrough pain may require a combination of pharmacological and nonpharmacological treatment strategies; supplemental analgesia, known as rescue medication, is a common pharmacological treatment option. The ideal rescue medication should have a rapid onset, good efficacy, relatively short duration of action, and minimal adverse effects and is best administered before or soon after breakthrough pain has started. Although oral opioids are commonly used, there is increasing evidence that transmucosal opioids may be more effective. Breakthrough is a common heterogeneous pain state that can have a devastating impact on both patients and carers. Despite the growing literature on breakthrough pain, there are still many aspects yet to be addressed including an urgent need to standardize terminology, for carefully designed epidemiological studies and for well designed controlled trials comparing the different treatment options.