K. Rufus. Dowling College.
Maybe a diferent mindset is thorities and insurance companies are responsible for needed to cope with products of such high complexity buy discount primaquine 15 mg. Pharmaceutical discount primaquine 15 mg with amex, bio- Or maybe new business models are required to gener- tech and medtech companies supply the system and ate proft with such products buy 15 mg primaquine mastercard. Now all par- A new competitor has emerged on the scene: medtech ties will need to join forces to ensure broad, high-quality companies. Some medtech companies are already one patient access using diferent means of integration, step ahead of Big Pharma. Indeed, the medtech industry such as digital platforms and new reimbursement seems to be better positioned to proft from regenerative schemes. Medtech companies do not depend on single be more important than ever, as healthcare systems will blockbuster products but generate profts with a large only pay for performance. These players are also used to design- Substantial changes are likely on the operations side. Re- ing customer-specifc solutions and adapting them to in- generative medicine, unlike current of-the-shelf phar- dividual needs, as is the case with surgical instruments. For many therapies, tive medicine, where combination products such as cellular material must frst be sourced from blood, bone engineered tissues are produced. This is unlikely to take place at the manufac- Future therapies involving regenerative medicine will turing sites of pharmaceutical companies. Instead, ini- require tools, techniques and agents that can be used tial processing will probably occur at the bedside in the in-house to ensure their broad availability and use. The procedure involved involving instruments and agents will be needed, and will require special training and investment in the nec- will be provided by the medtech industry. Or will peer-to-peer collaboration models investment both in infrastructure and in the education with Big Pharma succeed? Today, the race seems open and training of qualifed personnel is therefore re- and it also involves competing biotech companies and quired if patients are to be treated with regenerative leading research-driven healthcare providers. Regenerative medicine is a new and valuable treatment op- consortium HemAcure addresses a far more frequent disease, tion for more and more acute and chronic clinical conditions. HemAcure consists of aca- to signifcantly improve such chronic conditions as cartilage demic groups from Germany, Italy and the United Kingdom, defects or malignant melanomas. It is even possible to cure and uses a medical device supplied by a Canadian medtech certain diseases, such as some types of leukemia and a rare company. In terms of transplants, scientists have managed to tissue engineer the One European biotech company is even further along the frst autologous organ parts when donors were lacking. They road, with an allogenic stem-cell injection currently in the ap- have successfully constructed bladders, blood vessels, skin proval process. In fact, it is not impossible that we will see dis- An ex-vivo gene therapy approach has also been chosen by eases become extinct for which patients used to take daily another partnership between academia and industry. B: Regenerative medicine is set to transform the healthcare ecosystem Patient Payer Promises a cure Healthcare provider vs. The question must be answered separately for each treatment, based on the W e foresee far more target population size and the severity of the disease. However, the problems it raises and the need for nego- complex and integrated tiation between payers and providers of such therapies will be the same in each case. Unfortunately, this is not the way pharmaceu- tives will also be needed for the clinical laboratories tical remuneration works. Healthcare systems will sim- and hospital pharmacies involved in the event that ply not be capable of paying such linear extrapolations therapies need to be partially delivered on site. At some point, the fnan- Designing commercial models for these complex, cost- cial value will grow more slowly than the value the ther- ly therapies is likely to determine whether or not they apy provides to the patient. It also represents an The truth is that current reimbursement models are enormous chance for healthcare systems to work to- not ready for regenerative medicine. Roland Berger gether with the pharmaceutical and medtech industry foresees far more complex and integrated commercial to develop sophisticated win-win models that beneft remuneration models developing for regenerative everyone: pharmaceuticals and medtech suppliers, medicine in the future. This may be the only way to ensure that the providers of the therapy are sufciently reimbursed to keep them committed to it in the long run. Possible remuneration models for stem-cell and gene therapies include shared cost models, special fnanc- ing plans, milestone payment models and repayment models in the event of failure. Regenerative medicine Roland Berger Focus 13 The advent of regenerative medicine is a game changer Pharmaceutical companies should also adapt their or- for Big Pharma. Given the challenges it presents to ganizational model and people strategy to ensure the their established business model, we recommend that availability of appropriate skills, capabilities and ca- companies carry out an audit to determine their "ft" pacities in the new development, manufacturing and with the new world of regenerative medicine. Out-of-the-box thinking will come data and so on) and its overall organizational be necessary to secure their position in the future model and people strategy. They will need to fnd ed as necessary, depending on the specifc business and answers to some difcult questions: Should they ex- nature of the company. Based on the gaps identifed in pand their activities to include healthcare provision? What is the best way to steer their regenerative medi- Pharmaceutical companies have a number of aspects cine business in parallel with their traditional drug to consider. How can they engage more in sensors, devic- tablish ways to identify threats from products with es and diagnostics? What tools should they provide to substitution potential for their own therapeutics. They physicians and clinical staf to simplify medical treat- should also establish a mechanism for identifying the ments and the measurement of outcomes? Equally changes must be made to their legal structure or orga- important are searching for potential biochemical tar- nizational setup? This is an opportunity they cannot aford to bring their clinical development model into line with miss. Given the severity of interventions, they must place a special focus on long-term studies of safety. Thilo Kaltenbach Morris Hosseini Partner Partner +49 89 9230-8651 +49 30 39927-3342 thilo. Bastian Eulenstein Koen Besteman Senior Consultant Principal +49 89 9230-8151 +31 20 796 0619 bastian. The reader should not act according to any information provided in this publication without receiving specifc professional advice. Roland Berger GmbH shall not be liable for any damages resulting from any use of the information contained in the publication. Regenerative medicine Roland Berger Focus 15 About us Roland Berger, founded in 1967, is the only leading global consultancy of German heritage and European origin. With 2,400 employees working from 34 countries, we have successful operations in all major international markets. Navigating Complexity Roland Berger has been helping its clients to manage change for half a century. Looking forward to the next 50 years, we are committed to supporting our clients as they face the next frontier. We help our clients devise and implement responsive strategies essential to lasting success. There are a lot of applications in artificial intelligence domain that try to help human experts offering solutions for a problem.
The recently characterized latex allergen discount generic primaquine canada, Hev b 11 buy primaquine 15 mg with mastercard, shows endochitinase activity and may be involved in hydrolytic cleavage of chitin 15mg primaquine free shipping, the major structural component of the cell wall of many fungi as well as the exoskeleton of insects. Hevamine, a basic protein from the lutoid fraction, functions as a defense-related bifunctional enzyme with chitinase and lysozyme activity ( 94). Hevamine catalyzes the cleavage of b-1,4-glycosidic bonds of chitin and the sugar moieties of the cell surface peptidoglycans ( 95). Common Enzymes and Structural Proteins of Hevea Species Latex The proline-rich Hev b 5 with a predominantly random secondary structure shows a 46% amino acid sequence homology to an acidic protein from kiwi ( 96,97). The latex profilin Hev b 8 is the actin-binding protein and appears to involve in the organization of actin network of the plant cytoskeleton ( 98). Immunologic Evaluation of Latex Allergens in Health Care Workers and Spinal Bifida Patients The immune responses in latex-sensitized patients have recently been evaluated using purified recombinant allergens. The results of these studies confirm the specificity and reliability of purified allergens in the immunodiagnosis of latex allergy. However, the native counterpart appears as a tetramer of molecular mass of 58 kDa ( 99,100,101 and 102). Hev b 1 is a major allergen reacting with 81% of latex-sensitized spina bifida patients and 50% of health care workers ( 103). Depending on the method used, the reactivity varied from 20% to 61% of latex-allergic patients ( 104). Recombinant Hev b 2 overexpressed in a prokaryotic expression system failed to react with IgE from sera of latex-allergic patients ( 83). Hev b 3 The Hev b 3 protein is associated with the small rubber particles in latex and demonstrates a strong IgE-binding reactivity in spina bifida patients with latex allergy (107,108 and 109). The reactivity of Hev b 3 with serum IgE in health care workers is less frequent and weaker than in spina bifida patients ( 108,109). The amino acid sequence comparison of Hev b 3 demonstrated 47% sequence homology with another major allergen, Hev b 1, a component of large rubber particles (108). Recombinant Hev b 3 cloned and expressed in bacterial system exhibited specific binding to latex spina bifida patients (111). Hev b 4 Hev b 4 has been reported by Sunderasen and colleagues as a microhelix component of latex that is purified using the conventional method ( 105). It is an acidic protein and, under reducing condition, appeared as broad band of about 50 to 57 kDa. Hev b 5 The molecular cloning and expression of Hev b 5 has been reported independently by two investigators ( 96,97). This acidic protein is a major allergen with strong IgE-binding reactivity in both health care workers and spina bifida patients. In vivo IgE-binding property of Hev b 5 is evident from its strong histamine release from basophils in latex-allergic patients ( 96,112). Hev b 6 (Prohevein) Hev b 6 shows strong reactivity with IgE in health care workers and spina bifida patients with latex allergy ( 104). The results of skin test reactions correlated well with the in vitro IgE to latex allergens (82,113,114). Epitope mapping of the prohevein molecule revealed more IgE-binding regions near the N-terminal end of the protein ( 114). Hev b 7 Hev b 7, a patatin-like protein, showed IgE-binding reactivity with 23% of health care workers with latex allergy ( 115,116 and 117). Although both health care workers and spina bifida patients exhibited IgE binding with Hev b 7, this allergen recognized only a small group of patients, for whom IgE antibody against other major latex allergens could not be detected ( 112). Hev b 8 (Profilin) Profilins are actin-binding proteins involved in the formation of actin network of plant exoskeleton. The purified latex profilin, when used in skin-prick testing, showed positive reactions in all the 24 spina bifida patients and in 6 of 17 health care workers with latex allergy. The latex-derived profilin shows cross-reactivity with IgE from 36 patients with ragweed allergy (98). A high degree of cross-reactivity can be expected because of the homology of enolases present in different organisms (Cladosporium species) and plants (tomato). However, preliminary studies in our laboratory of 26 health care workers with latex allergy failed to show IgE binding with the recombinant latex and fungal enolases (unpublished results). This type 1 chitinase shares homology with N-terminal hevein domain and also shares epitopes with chitinases from avocado and banana ( 92,93). The cross-reactivity and immune responses of Hev b 11 in allergic reaction have not been fully elucidated; hence, it is designated as a minor allergen in latex allergy. This 30-kDa protein exhibits extensive sequence homology with chitinase and lysozymes from various sources (75,83). Purified hevamine demonstrated IgE reactivity with only 1 in 29 latex-allergic sera tested and hence are not considered as an important allergen in inducing latex allergy ( 83). The lack of a hevein-like domain near the N-terminal region of the protein may be responsible for its minimal allergenicity in latex-allergic patients. Several other latex allergens have been identified by two-dimensional immunoblotting and microsequencing ( 75). These proteins with sequence similarities to spinach, rice, and tomato triose phosphate isomerases and several proteosane subunits are yet to be purified and characterized for their role in latex allergy. Two-dimensional immunoblot demonstrates more than 200 peptides, with more than 50 spots demonstrating immune reactivity with IgE. This widespread cross-reactivity among various plant proteins may be due to the presence of common T- and B-cell epitopes in them. Although extensive work has been carried out to identify the proteins involved in latex allergy, not much information is available on the cross-reactivity of latex allergens with proteins from other sources. In a recent study, Beezhold and associates demonstrated the co-sensitization between latex and various foods by skin-prick testing ( 120). Cross-reactive allergens in banana appear in several molecular weight ranges between 23 and 47 kDa and in avocado between 27 and 91 kDa ( 121,122 and 123). Akasawa and colleagues identified an avocado chitinase as one of the cross-reacting proteins using sera from latex-allergic patients ( 124). Yagami and co-workers proposed that the pathogenesis-related latex proteins such as chitinase and b-1,3-glucanase are potential cross-reacting proteins because they are common in different plant families and have comparable amino acid sequences and immunologic properties (91). In a recent study, Blanco and colleagues showed that chestnut and avocado type 1 chitinases with N-terminal hevein-like domain are the major allergens that cross-react with latex and suggested that type 1 chitinases are the pan allergens responsible for the latex-fruit syndrome ( 119). The cross-reactivity between fruits, pollen, and latex is also attributed to the highly conserved plant allergen profilin identified in all these different species ( 30). These results demonstrated a mutual boosting effect of pollen and latex sensitization in vivo, which may be seen also in polysensitized plant allergic patients. This study confirmed that mice stimulated with latex proteins develop a predominantly T H2 cytokine response. The results indicated that eosinophils and IgE antibodies play a major role in the immunopathogenesis of latex-induced allergy and anaphylaxis.
Normally generic primaquine 15 mg with mastercard, the load faced by the chest bellows is so low that ventilation occurs effortlessly buy 15 mg primaquine. Stiff lungs or increase airway resistance results in an increased workload and depending on the magnitude of the load and other factors order 15mg primaquine with amex, the chest bellows may fail resulting in respiratory failure. Normally room air is 21% oxygen and the partial pressure of oxygen in arterial blood (PaO2) at sea level is ~90mmHg. For practical purposes, hypoxemic respiratory failure is considered to be present if PaO2 cannot be corrected to >50mmHg on a nontoxic level of supplemental oxygen (<50%). Hypercapnic respiratory failure is characterized by elevated levels of carbon dioxide in arterial blood. It is often accompanied by hypoxemia, though typically not as severely as is the case in hypoxemic respiratory failure. Types of Respiratory Failure Hypoxemic Hypercapnic Characterized by Hypoxemia (arbitrarily Characterized by Hypercapnia (>46mmHg) and <50mmHg) hypoxemia (usually) Typical Causes. The two types of respiratory failure also differ as to the conditions or diseases that typically produce them. Hypercapnic Respiratory Failure The common causes of hypercapnic failure are diseases of any of the components of the respiratory system leading up to the lungs: the brainstem, the respiratory muscles, the chest wall, or the airways (see Table 4-5. In hypercapnic respiratory failure, relatively mild hypoxemia occurs, primarily for the same reason that hypercapnia occurs: the level of ventilation is not adequate to refresh the oxygen within the lungs, just as it is not adequate to eliminate a normal amount of carbon dioxide. Hypercapnic respiratory failure results when the ventilatory pump is inadequate to meet the metabolic and ventilatory demands because of reduced central drive (brain), impaired respiratory muscle function (nerves or muscles), excessive respiratory workload, or some combination of these three factors2 (Table 4-5. Of the three potential causes of hypercapnic respiratory failure, the least common is impaired central drive. Unfortunately, symptoms correlate poorly with the severity of respiratory failure. Cyanosis of the mucous membranes and nail beds is an unreliable sign of hypoxemia. They allow for precise assessment of the adequacy of oxygenation, along with determination of acid/base status and of the adequacy of ventilation. Drawbacks are the painful nature of the necessary arterial puncture, the small risk of arterial injury, and the fact that they provide only a snapshot look at the status of respiratory function. Thus, although bicarbonate measurements without blood gases do not rule in or rule out respiratory failure, a normal venous bicarbonate can be reassuring, especially when the pulse oximeter reading is normal and the patient s mental status is well preserved. Pulse oximetry is a noninvasive technique to allow measurement and monitoring of blood oxygen (SpO2). A patient s fingertip is transilluminated by two wavelengths of light, typically 660nm (red) and approximately 900 nm (infrared), in rapid alternation. Changes in absorbance of each of the two wavelengths, caused by pulsing arterial blood is measured, and the ratio of the two is used to calculate percent oxygen saturation. It can quickly rule in or rule out most cases of hypoxic respiratory failure and those cases of hypercapnic respiratory failure where the oxygen level is also low. Pulmonary function testing is usually valuable in the evaluation of the underlying pulmonary condition(s) that cause or contribute to respiratory failure. Severe reductions suggest pulmonary parenchymal disease (pneumonia, pulmonary fibrosis, etc. Thus, central drive impairment due to drug overdose can often by treated by specific antidotes (e. Adjunctive treatments, especially the administration of supplemental oxygen, can be beneficial, while awaiting improvement in the underlying disease or in the situations in which the underlying disease cannot be corrected. The FiO2 actually delivered by nasal cannulae is quite variable and not reliably predictable by the liter per minute flow rate, in part because of variable amounts of mouthbreathing, but more importantly because inspiratory flow rates and consequent entrainment of room air are tremendously variable. The Venti-mask uses a jet of oxygen at high flow rate (5-15 liters per minute) through a delivery device shaped to entrain predictable amounts of room air (using the Venturi principle), so that FiO2 can be adjusted relatively precisely. The Venti-mask results in more predictable FiO2 than does nasal cannula, but it still suffers from entrainment of variable amounts of room air around the edges of the mask and through the holes that are built into the mask to allow egress of excess flow. The non-rebreather mask provides 100% oxygen from a bag reservoir into the mask and uses one-way valves to direct exhaled gases out of the mask. Even a non-rebreather mask, however, entrains a variably small but not negligible amount of room air around the mask and through one of the expiratory one-way valves, which is routinely left open so as to avoid suffocation if the reservoir runs dry. Supplemental oxygen is the major adjunctive treatment for respiratory failure, and in patients with hypoxic respiratory failure, it can be used safely (for short periods) at any dose and for indefinite periods at nontoxic concentrations (FiO2 <50%). For the hypoxemia that often accompanies the hypercapnic type of respiratory failure, however, oxygen must be used with more caution. Consequently, their ventilatory drive is based primarily on oxygenation with low levels of oxygen stimulating increased breathing. For that reason, in hypercapnic respiratory failure (and in persons suspected of having hypercapnic respiratory failure in whom blood gases have not been measured), oxygen must be administered at low enough flow rates or FiO2 to avoid over-oxygenation. In practice, pulse oximetry is used to guide oxygen therapy, aiming for a pulse oximetriy reading (SpO2) that is safe but less than normal, 88 - 93% in persons with hypercapnic respiratory failure. Mechanical support is most clearly indicated in hypercapnic respiratory failure, but it can also be beneficial for hypoxemic respiratory failure, by blowing open collapsed regions of the lung and by improving the distribution of ventilation even in regions already open. In addition to correcting hypoxemia and hypercapnia, there are other benefits of mechanical ventilatory support, including: Maintenance of oxygenation and acid/base balance Comfort Improved sleep Prevention of inspiratory muscle fatigue Perhaps most important is the comfort issue. Dyspnea (shortness of breath) comes in many different varieties and has many potential physiologic causes, but in hypercapnic respiratory failure, one of the main problems appears to be the perception of the need for excessive respiratory effort. Although me- chanical ventilation does not totally take over the work of breathing, it can substantially reduce the load on the respiratory muscles, especially if adequate inspiratory flow rates are used. Mechanical ventilatory support also has a clear and established role in obstructive sleep apnea, being able to splint the upper airways open, preventing the upper airway collapse that is the major pathophysiologic cause of obstructive sleep apnea. Invasive Mechanical Ventilatory Support Ventilatory support can be accomplished by noninvasive or invasive means, the latter via endotracheal intubation or tracheostomy. The noninvasive techniques have the advantages of (usually) less discomfort, preserved ability to talk and to cough, less risk of airway (laryngeal and tracheal) injury and of ventilator associated pneumonia and the likelihood that the duration of support will be shorter (Table 4-5. When respiratory failure is severe, noninvasive methods are just not adequate to provide the necessary volumes to correct it. With invasive mechanical ventilation, although secretions can still be aspirated alongside the endotracheal or tracheostomy tube, the risk of massive aspiration is considerably less than with noninvasive techniques. There is also easier access to secretions, both for culture and for therapeutic purposes. The advantage over the previously-available pressure ventilation, is that the ventilator adapts to changing mechanics by essentially guaranteeing the delivery of a reasonable tidal volume, thereby avoiding the unexpected hypoventilation that were problems of the old pressure ventilation mode. A disadvantage is that over-ventilation is a constant threat; every effort by the patient results in a full tidal volume, so patients with severe shortness of breath often are found to over-breathe or over-ventilate, with consequent respiratory alkalosis (hypocapnia), elevated pressures and subsequent difficulties with weaning. Another disadvantage is that patients who are not sedated often find the set flow rates too low to satisfy their perceived need, so shortness of breath and discomfort may persist, despite mechanical ventilation. Specialized Modes A number of specialized modes of mechanical ventilation have been developed but are beyond the scope of this chapter. To date, none has been unequivocally demonstrated to improve outcomes over conventional modes.
Physiotherapy is the treatment of choice for musculoskeletal symptoms accompanying fre- quent episodic or chronic tension-type headache order 15 mg primaquine fast delivery. In stress-related illness order genuine primaquine, lifestyle changes to reduce stress buy primaquine no prescription, and relaxation and/or cognitive therapy to develop stress-coping strategies, are the treatment mainstays. Amitriptyline is rst-line in most cases, withdrawn after improvement has been maintained for 4 6 months. Long-term remission is not always achievable, especially in long-standing chronic tension-type headache. Cluster headache Because of its relative rarity, cluster headache has a tendency to be misdiagnosed, sometimes for years. It is the one primary headache that may not be best managed in primary care, but the primary care physician has an important role not only in recognizing it at once but also in discour- aging inappropriate treatments (tooth extraction is not infrequent). Medication-overuse headache Prevention is the ideal management of medication-overuse headache, which means avoidance of acute medication for headache on more than 2 3 days per week on a regular basis. Education is the key factor: many patients with medication-overuse headache are unaware of it as a medical condition (40). Once this disorder has developed, early intervention is important since the long- term prognosis depends on the duration of medication overuse (41). Although this will lead initially to worsening headache and sometimes nausea, vomiting and sleep disturbances, with forewarning and explanation it is probably most successful when done abruptly (42). Follow-up is essential, at intervals balanced on the one hand to allow time for treatment interventions to achieve observable effect and on the other to meet patients natural desires for a quick solution to a painful and often debilitating problem. For migraine and episodic tension-type headache, attack frequency is likely to be the principal determinant. For chronic tension-type headache, follow-up provides the psychological support that is often needed while recovery is slow. During later follow-up, the underlying primary headache condition is likely to re-emerge and require re-evaluation and a new therapeutic plan. Most patients with medication-overuse headache require extended support: the relapse rate is around 40% within ve years (41). Urgent referral for specialist management is recommended at each onset of cluster headache. Weekly review is unlikely to be too frequent and allows dosage incrementation of potentially toxic drugs to be as rapid as possible. Patients commencing lithium therapy, or changing their dose, need levels checked within one week. In all other cases, specialist referral is appropriate when the diagnosis remains (or becomes) unclear or these standard management options fail. The common headache disorders require no special investigation and they are diagnosed and managed with skills that should be generally available to physicians. Management of headache disorders therefore belongs in primary care for all but a very small minority of patients. Models of health care vary but, in most countries, primary care has an acknowledged and important role. It is a role founded on recognition that decisions in primary care take account of patient-related factors family medical history and patients individual expectations and values of which the continuity and long-term relationships of primary care generate awareness (43) while promoting trust and satisfaction among patients (44). Even in primary care, however, the needs of the headache patient are not met in the time usu- ally allocated to a physician consultation in many health systems. In order to implement benecial change, public health policy in all countries must embrace the following elements. In the case of the medical profession, this should begin in medical schools by giving headache disorders a place in the undergraduate curriculum that matches their clinical importance as one of the most common causes of consultation. Their outcomes should be evaluated in terms of measurable reductions in population burden attributable to headache disorders. Aside from this partnership, lay and professional groups in countries around the world play im- portant, though often less formal, roles in education and in sharing information and experience. The results will guide appropriate allocation of health-care resources by policy-makers. Epidemiological studies may also identify preventable risk factors for headache disorders. This is particularly so given the prevalence of medication misuse (both underuse and overuse). Community intervention studies may lead to better prevention of headache disorders. The importance of patient and public involvement in dening research objectives should be emphasized: lay people have experience and skills that complement those of researchers. They have a neurological basis, but headache rarely signals serious underlying illness. The huge public health importance of headache disorders arises from their causal association with personal and societal burdens of pain, disability, damaged quality of life and n a n c i a l c o s t. They are diagnosed clinically, requiring no special investigations in most of the cases. Nurses and pharmacists can complement the delivery of health care by primary care physicians. Mismanagement, and overuse of medications to treat acute headache, are major risk factors for disease aggravation. Cost-of-illness studies will create awareness of the potential savings that better health care for headache disorders may achieve through mitigated productivity losses. American Association for the Study of Headache and International Headache Society. The global burden of headache: a documentation of headache prevalence and disability worldwide. The prevalence and disability burden of adult migraine in England and their relationships to age, gender and ethnicity. Prevalence of primary headache syndrome in adults in the Qassim region of Saudi Arabia. Evidence-based guidelines in the primary care setting: neuroimaging in patients with nonacute headache. Lost workdays and decreased work effectiveness associated with headache in the workplace. Neurological services and the neurological health of the population in the United Kingdom. Patterns of health care utilization for migraine in England and in the United States. Impact of headache on sickness absence and utilisation of medical services: a Danish population study. Guidelines for all doctors in the diagnosis and management of migraine and tension-type headache. Aspirin in episodic tension-type headache: placebo-controlled dose-ranging comparison with paracetamol. Long-term outcome of patients with headache and drug abuse after inpatient withdrawal: v e - y e a r f o l l o w - u p.