Neck Pain in Adolescent Headache Sufferers. A Cohort Study of Schoolchildren

Although neck pain (NP) and headache (HA) are often concomitant in adolescents, few data exist on the association of NP with HA in this age group. The aim of the study was to examine the association of concomitant NP with adolescent HA and with the outcome of HA. The associations of self-reported NP, physical findings of the neck and disc degeneration of the cervical spine with adolescent HA were studied. This study is part of a population-based follow-up study of 12-year-old children (N 1135/1409) with and without HA. A sample of adolescents (N = 304) was followed to the age of 16 years. At the age of 17 years, 69 of them participated in a magnetic resonance imaging (MRI) study of the cervical spine. During the follow-up from 13 to 16 years of age, changes in both HA type and frequency were common. A poor outcome of HA was associated with NP interfering with daily activities at the age of 13 years. The changes in HA type were not predictable by NP. At the age of 16 years, local and referred palpation pain of the neck muscles, self-reported NP and NP intensity were associated with HA, and especially with disturbing HA unresponsive to analgesics. The association of NP with HA was not determined by HA type. Mild degenerative changes of the cervical spine were common but did not contribute to headache. HA in adolescence is often episodic, and prevention and treatment of NP could be important in the prevention of future chronic adult HA.

Temporomandibular Disorders and Headache in Adolescents

13-16-vuotiaiden purentaelimistön toimintahäiriöt ja päänsärky Tutkimuksen tarkoituksena oli selvittää purentaelimistön toimintahäiriöihin (TMD) liittyvien oireiden ja kliinisten löydösten esiintyvyyttä ja muutosta kolmen vuoden seurannan aikana päänsärystä kärsivillä nuorilla ja heidän verrokeillaan, TMD-löydösten yhteyttä eri tyyppisiin päänsärkyihin ja päänsärkyyn liittyviin tekijöihin, TMD-löydöksiä ennustavia tekijöitä sekä perhetaustan osuutta TMD-löydösten esiintyvyyteen. Tutkimus perustui kahteen laajaan koululaismateriaaliin Turun seudulla. Ensimmäinen 13-vuotiaiden nuorten ryhmä (n = 311) osallistui myös 16-vuotiaana seuranta-tutkimukseen. Toisen 13-vuotiaiden nuorten ryhmän (n = 154) äidit (n = 154) osallistuivat myös tutkimukseen, jossa selvitettiin tapaus-verrokkiasetelmassa TMD-löydösten ja päänsärkyjen esiintyvyyttä kahdessa sukupolvessa. Nuoret jaettiin päänsärkyryhmiin ja terveisiin kontrolleihin IHS (1988) päänsärky-kriteerien mukaisesti kyselykaavakkeen ja lääkärin suorittaman haastattelun ja kliinisen tutkimuksen antamien tietojen perusteella. Lääkäri määritteli äitien päänsärkydiagnoosin kyselykaavakkeen tietojen perusteella. Kaikki nuoret ja heidän äitinsä haastateltiin ja heille tehtiin kliininen purentafysiologinen tutkimus sokkoutetusti. Tutkimuksen tulokset osoittivat, että tytöillä esiintyi TMD-löydöksiä selvästi enemmän kuin pojilla sekä ennen puberteettia että sen jälkeen. Tutkimuksessa havaittiin selkeä yhteys TMD-löydösten ja molempien päänsärkytyyppien, migreenin ja episodisen tensiotyyppisen päänsäryn, välillä. Kolmen vuoden seurannan aikana TMD-löydöksissä havaittiin runsasta muutosta ja iän myötä vähenemistä, mutta TMD-oireiden kohdalla ei vastaavaa muutosta todettu. TMD-löydösten ja niska-hartiaseudun lihaskipujen välillä havaittiin yhteys 13-vuotiailla nuorilla. Mikään päänsärkyyn liittyvistä tekijöistä 13-vuotiailla ei osoittautunut ennustavaksi taustatekijäksi myöhemmille TMD-löydöksille. TMD-löydösten suhteen ei todettu perheyhteyttä. Päänsäryistä kärsivillä nuorilla on enemmän myös muita kiputiloja, kuten purentaelimistön toimintahäiriöitä ja niska-hartiaseudun kipuja, kuin heidän terveillä verrokeillaan. 1316 vuoden iässä nämä löydökset ovat valtaosaltaan lieviä ja vaihtelevia.

Neck Muscle Function and Adolescent Headache

Muscular function of the neck region may be of importance for the etiology of headache, especially of tension-type headache. However, very few data exist on the association of neck muscle function with different types of headache in adolescents. The main aim of the study was to examine the association of neck muscle function with adolescent headache. The associations between leisure time activities, endurance strength of the upper extremities (UE endurance) and mobility of the neck-shoulder region and adolescent headache were studied. In addition, the associations of force production, EMG/force ratio, co-activation and fatigue characteristics, and cross-sectional area (CSA) of neck muscles with adolescent headache were studied. The study is part of a population-based cohort study of 12-year-old children with and without headache. The study had five phases (years 1998-2003). At the age of 13 years, a sample of 183 adolescents (183/311) participated in endurance strength and mobility measurements of the neck-shoulder region. In addition, the type and level of physical and other leisure activity were elicited with open and structured questions. At the age of 17 years, a random sample of 89 adolescents (89/202) participated in force and EMG measurements of the neck-shoulder muscles. In addition, at the age of 17 years, a sample of 65 adolescents (65/89) participated in CSA measurements of the neck muscles. At the age of 13 years, intensive participation in overall sports activity was associated with migraine. Frequent computer use was associated both with migraine and tension-type headache. The type of sports or other leisure activity classified them on the basis of body loading was not associated with headache type. In girls, low UE endurance of both sides, and low cervical rotation of the dominant side, were associated with tension-type headache, and low UE endurance of non-dominant side with migraine. In boys, no associations occurred between UE endurance and mobility variables and headache types. At the age of 17 years, in girls, high EMG/force ratios between the EMG of the left agonist sternocleidomastoid muscle (SCM) and maximal neck flexion and neck rotation force to the right side as well as high co-activation of right antagonist cervical erector spinae (CES) muscles during maximal neck flexion force were associated with migraine-type headache. In girls, neck force production was not associated with headache types but low left shoulder flexion force was associated with tension-type headache. In boys, no associations were found between EMG and force variables and headache. Increased SCM muscles fatigue of both sides was associated with tension-type headache. In boys, the small CSA of the right SCM muscle and, in girls, of combined right SCM and scalenus muscles was associated with tension-type headache. Similarly, in boys, the large CSA of the right SCM muscle, of the combined right SCM and scalenus muscles, of the left semispinalis capitis muscle, of the combined left semispinalis and splenius muscles was associated with migraine. No other differences in the CSA of neck flexion or extension muscles were found. Differences in the neuromucular function of the neck-shoulder muscles were associated with adolescent headache, especially in girls. Differences in the cross-sectional area of unilateral neck muscles were associated with headache, especially in boys. Differences in the neuromuscular function and in the cross-sectional area of the neck muscles also occurred between different types of headache. It remains to be established whether the findings are primary or secondary to adolescent migraine and tension headache. Keywords: adolescent, cross-sectional area, electromyography, endurance strength, fatigue, force, headache, leisure time activity, migraine, mobility, neck muscles, tension-type headache

Epidemiological studies of childhood and adolescence headache

The main purpose of this study was to examine the changes in the prevalence, incidence, and characteristics of headache in childhood and adolescence. In addition, the predictors of the change in the occurrence of childhood headache and the association between adolescent headache and behavior were studied. The occurrence and characteristics of headache were investigated as part of a prospective follow-up study, where 6-year-old children and their families (n=1132) were followed to the age of 12-years (n=1126). The study design entailed both a cohort and case-control group. The incidence of headache and the association between headache and behavior were studied in another cohort, consisting of 11-year-old twins (n=5393), who were followed to the age of 17 (n=4159). The prevalence rates of headache increased during the follow-up, especially in boys whose mothers suffered from frequent headache. The incidence rates of frequent headache changed the most in girls between ages of 11 and 14. Early-onset migraine and tension-type headache were equal predictors of migraine at age 12. The age-related changes observed in pain localization, concurrent symptoms and triggers were considerable. Headache frequency was significantly associated with externalizing and internalizing problem behaviors and adaptive behaviors as rated by parents, but only with externalizing problem behaviors as rated by teachers. Headache both in children and adolescents is characterized by its changing nature. Its prevention and treatment should take familial, environmental and psychosocial aspects into account.

A Comparative Study of the Effectiveness of a Prefabricated Appliance and a Stabilization Appliance in the Treatment of Myofascial pain and Headache

The aim of this thesis was to evaluate the short- and long-term effectiveness of a prefabricated occlusal appliance (R) on patients with myofascial pain and headache by comparing it with the treatment of the stabilization appliance (S). Another aim was to evaluate the effect of appliance treatment on stress-related salivary parameters like cortisol and IgA, as well as on flow rate values in these patients. Sixty-five patients diagnosed with myofascial temporomandibular disorder (TMD) pain, of whom 94% suffered concomitantly from headache, at two centres for Stomatognathic Physiology, one in Sweden and one in Finland, were included in this randomized controlled trial using Research Diagnostic Criteria for TMD (RDC/TMD), with history questionnaires and clinical examinations performed at baseline and at 6- and 10-weeks, and 6- and 12-month follow-ups. Patients were randomly assigned either to the R or the S group. Treatment outcome was measured according to IMMPACT (Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials), i.e. four chronic pain outcome domains: pain intensity, overall improvement, physical and emotional functioning. Changes in frequency and intensity of headache were recorded. Thirty-nine patients participated in the saliva study. Salivary analyses were performed at 6 and 10 weeks. The results revealed no differences between groups at baseline. At all follow-ups, all four outcome measures, as well as frequency and intensity of headache, showed statistically significant within-group improvement compared to baseline, without significant differences between groups. No treatment-induced changes in saliva parameters could be registered. In conclusion, the effectiveness of the prefabricated appliance seemed to be similar to that of the stabilization appliance in alleviating myofascial pain, and frequency and intensity of headache, in the short as well as the long term. However, no changes in salivary parameters were observed during treatment.

Secondary Aural Symptoms in Relation to Cranio-Cervical and General Disorders

The present thesis comprises two study populations. The first study sample (SS1) consisted of 411 adults examined and interviewed at three annual visits. The second study sample (SS2) consisted of 1720 adults who filled in a mailed questionnaire about secondary otalgia, tinnitus and fullness of ears. In the second phase of the SS2, 100 subjects with otalgia were examined and interviewed by specialist in stomatognathic physiology and otorhinolaryngology. In the third phase, 36 subjects participated in a randomized, controlled and blinded trial of effectiveness of occlusal appliance on secondary otalgia, facial pain, headache and treatment need of temporomandibular disorders (TMD). The standardized prevalence of recurrent secondary otalgia was 6%, tinnitus 15% and fullness of ears 8%. Aural symptoms were more frequent among young than old subjects. They were associated with other, simultaneous aural symptoms, TMD pain, head and neck region pain, and visits to a physician. The subjects with aural symptoms more often had tenderness on palpation of masticatory muscles and clinical signs of temporomandibular joint than the subjects without. 85% of the subjects reporting secondary otalgia had cervical spine or temporomandibular disorder or both. In SS1, the final model of secondary otalgia included active need treatment for TMD, elevated level of stress symptoms, and bruxism. In SS2, the final models of aural symptoms included associated aural symptoms, young age, TMD pain, headache and shoulder ache. Stabilization splint more effectively alleviated secondary otalgia and active treatment need for TMD than a palatal control splint. In patients with aural pain, tinnitus or fullness of ears, it is important to first rule out otologic and nasopharyngeal diseases that may cause the symptoms. If no explanation for aural symptoms is found, temporomandibular and cervical spine disorders should be rouled out to minimize unnecessary visits to a physician.

Kotona asuvien iäkkäiden monilääkitys sekä psyyken- ja kipulääkkeiden käyttö

Summary: Polypharmacy and the use of psychotropics and analgesic drugs among the community-dwelling elderly

A Diagnostic view of the Genetics of CASADIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, OMIM #125310) is an inherited vascular disease. The main symptoms include migraineous headache, recurrent strokes and progressive cognitive impairment. CADASIL is caused by mutations in the NOTCH3 gene which result in degeneration of vascular smooth muscle cells, arteriolar stenosis and impaired cerebral blood flow. The aims of this study were assessment of the genetic background of Finnish and Swedish CADASIL patients, analysis of genetic and environmental factors that may influence the phenotype, and identification of the optimal diagnostic strategy. The majority of Finnish CADASIL patients carry the p.Arg133Cys mutation. Haplotype analysis of 18 families revealed a region of linkage disequilibrium around the NOTCH3 locus, which is evidence for a founder effect and a common ancestral mutation. Despite the same mutational background, the clinical course of CADASIL is highly variable between and even within families. The association of several genetic factors with the phenotypic variation was investigated in 120 CADASIL patients. Apolipoprotein E allele 4 was associated with earlier occurrence of strokes, especially in younger patients. Study of a pair of monozygotic twins with CADASIL revealed environmental factors which may influence the phenotype, i.e. smoking, statin medication and physical activity. Knowledge of these factors is useful, since life-style choices may influence the disease progression. The clinical CADASIL diagnosis can be confirmed by detection of either the NOTCH3 mutation or granular osmiophilic material by electron microscopy in skin biopsy, although the sensitivity estimates have been contradictory. Comparison of these two methods in a group of 131 diagnostic cases from Finland, Sweden and France demonstrated that both methods are highly sensitive and reliable.

The Role of Cytochrome P450 3A Inducers and Inhibitors in the Metabolism and the Effects of Oxycodone

Oxycodone is an opioid used in the treatment of moderate or severe pain. It is principally metabolized in the liver by cytochrome P450 3A (CYP3A) enzymes whereas approximately 10% is metabolized by CYP2D6. Little is known about the interactions between oxycodone and other drugs, herbals and nutritional substances. In this work the effects of CYP3A inducers rifampicin and St. John’s wort and CYP3A inhibitors voriconazole, grapefruit juice, ritonavir and lopinavir/ritonavir were investigated on the pharmacokinetics and pharmacodynamics of oxycodone. All studies were randomized, balanced, placebo-controlled crossover clinical studies in healthy volunteers. The plasma concentrations of oxycodone and its metabolites were determined for 48 hours and pharmacodynamic parameters were recorded for 12 hours in each study. Pharmacokinetic parameters were calculated by noncompartmental methods. Rifampicin decreased the plasma concentrations, analgesic effects, and oral bioavailability of oral oxycodone. St. John’s wort reduced the concentrations of oxycodone and diminished the self-reported drug effect. Voriconazole increased the exposure to oral oxycodone by 3.6-fold whereas grapefruit juice, which inhibits predominantly the intestinal CYP3A, elevated the mean concentrations of oxycodone by 1.7-fold. Ritonavir and lopinavir/ritonavir increased the mean AUC of oxycodone by 3.0- and 2.6-fold, respectively, and prolonged its elimination half-life. In spite of increased oxycodone plasma concentrations during concomitant administration of CYP3A inhibitors, the analgesic effects were not increased. These studies show that the induction or inhibition of CYP3A alters the pharmacokinetics and pharmacologic effects of oxycodone. The exposure to oxycodone decreased after induction and increased after inhibition of CYP3A. As a conclusion, the clinicians should avoid concomitant administration of CYP3A inducers or inhibitors and oral oxycodone. If this is not possible, they should be prepared to interactions leading to impaired analgesia after CYP3A inducers or increased adverse effects after CYP3A inhibitors and oral oxycodone.

Pharmacokinetics of Oxycodone and Paracetamol in the Elderly. Clinical Pharmacokinetic Study on Orthopaedic Surgical Patients and Healthy Volunteers

The proportion of elderly people over 65 years of age in Finland is expected to grow to over 25% by the 2025. It has been estimated that elderly people today consume nearly 40% of all drugs. Age brings about number of physiological changes that may affect the disposition, metabolism and excretion of drugs. The function of heart, lungs, liver and kidneys decreases even in healthy people, as they get older. The proportion of total body water decreases and the relative fat percentage increases. Also several other factors such as concurrent diseases, concomitant medication and nutritional factors have an effect on drug therapy in elderly. Age increases the risk of adverse drug reactions, which most often are dose-dependent. Despite all this there are not enough studies involving the elderly people and the elderly are most often excluded from clinical trials. Oxycodone is a strong opioid analgesic, which is used to treat moderate or severe pain. Paracetamol is a widely used nonopioid analgesic, which has become popular in the treatment of pain in many patient groups. In this series of studies the pharmacokinetics of oral and intravenous oxicodone as well as intravenous paracetamol in the elderly and young adult patients were investigated. Also a study investigating the interaction of oral antibiotic clarityhromycin, a known cytochrome P450 (CYP) 3A4 inhibitor, with oxycodone pharmacokinetics and pharmacodynamics in elderly and young healthy volunteers was carried out. The pharmacokinetics of oxycodone showed a clear age depency. Patients over 70 years had 50-80% higher mean exposure to oral oxycodone and a twofold greater plasma concentration than young adults 12 h after ingestion of the drug. Elderly patients had 40-80% greater exposure to intravenous oxycodone and patients over 80 years had over twofold greater plasma concentrations 8 h post dose than the young adults. The elderly patients had also greater exposure to intra venous paracetamol compared to young adults. Clarithromycin increased the exposure to oral oxycodone in both young and elderly volunteers. The elderly had marked interindividual variation in the pharmacokinetics and pharmacodynamics when clarithromycin was given concomitantly with oxycodone. Because the pharmacokinetics of oxycodone and intravenous paracetamol depend on the age of the subject, it is important to titrate the analgesic dose individually in the elderly.

Pain symptoms and sleep problems among school-aged children. Long-term prevalence changes, and pain symptoms as predictors of later mental health

Children’s pain symptoms and sleep problems are among the most common health complaints. They distract children from activities, decrease the quality of life, contribute to a significant economic burden, and have shown continuity into adulthood. The main aims of this thesis were to investigate long-term changes in the prevalence of pain symptoms and sleep problems among Finnish school-aged children, and the later mental health of those who in childhood experience pain. Prevalence, co-occurrence, and associated psychosocial factors of pain symptoms and sleep problems were also assessed. In study I, prevalence changes in eight-year-old children’s pain symptoms and sleep problems were investigated in three cross-sectional population-based samples (years 1989: n=1038, 1999: n=1035, and 2005: n=1030). In study II, cross-sectional associations between pain symptoms, sleep problems, and psychosocial factors were assessed among 13-18-year-old adolescents (n=2476). In studies III and IV, associations between pain symptoms at age eight (n=6017), and register-based data on antidepressant use and severe suicidality by age 24, were examined in a nationwide birth cohort. Pain symptoms and sleep problems were common and often co-occurred. A considerable number of children’s pain symptoms remained unrecognized by the parents. The prevalence of pain symptoms, sleep problems, and multiple concurrent symptoms approximately doubled from 1989 to 2005. Psychiatric difficulties or demographic factors did not explain the increase. Psychosocial factors that were associated with pain, sleep problems, and a higher number of symptoms, were female sex, psychological difficulties, emotional symptoms, smoking, victimization, and feeling not cared about by teachers. In longitudinal analyses, the child’s own report of headache, and to a smaller degree the parental report of the child’s abdominal pain predicted later antidepressant use. Parental report of the child’s abdominal pain predicted severe suicidality among males. If one of the symptoms is present, health care professionals should inquire about other symptoms as well. Questions should be directed to the children, not only to their parents. Inquiring about psychiatric difficulties, substance use, victimization, and relations with teachers should be included as a part of the assessment. Further studies are needed to clarify the reasons that underlie the increased prevalence rates, and the factors that may increase or decrease the risk for later mental health problems among pain-suffering children.

Development and characterization of thin printed films for gas sensing applications

The monitoring and control of hydrogen sulfide (H2S) level is of great interest for a wide range of application areas including food quality control, defense and antiterrorist applications and air quality monitoring e.g. in mines. H2S is a very poisonous and flammable gas. Exposure to low concentrations of H2S can result in eye irritation, a sore throat and cough, shortness of breath, and fluid retention in the lungs. These symptoms usually disappear in a few weeks. Long-term, low-level exposure may result in fatigue, loss of appetite, headache, irritability, poor memory, and dizziness. Higher concentrations of 700 - 800 ppm tend to be fatal. H2S has a characteristic smell of rotten egg. However, because of temporary paralysis of olfactory nerves, the smelling capability at concentrations higher than 100 ppm is severely compromised. In addition, volatile H2S is one of the main products during the spoilage of poultry meat in anaerobic conditions. Currently, no commercial H2S sensor is available which can operate under anaerobic conditions and can be easily integrated in the food packaging. This thesis presents a step-wise progress in the development of printed H2S gas sensors. Efforts were made in the formulation, characterization and optimization of functional printable inks and coating pastes based on composites of a polymer and a metal salt as well as a composite of a metal salt and an organic acid. Different processing techniques including inkjet printing, flexographic printing, screen printing and spray coating were utilized in the fabrication of H2S sensors. The dispersions were characterized by measuring turbidity, surface tension, viscosity and particle size. The sensing films were characterized using X-ray photoelectron spectroscopy, X-ray diffraction, atomic force microscopy and an electrical multimeter. Thin and thick printed or coated films were developed for gas sensing applications with the aim of monitoring the H2S concentrations in real life applications. Initially, a H2S gas sensor based on a composite of polyaniline and metal salt was developed. Both aqueous and solvent-based dispersions were developed and characterized. These dispersions were then utilized in the fabrication of roll-to-roll printed H2S gas sensors. However, the humidity background, long term instability and comparatively lower detection limit made these sensors less favourable for real practical applications. To overcome these problems, copper acetate based sensors were developed for H2S gas sensing. Stable inks with excellent printability were developed by tuning the surface tension, viscosity and particle size. This enabled the formation of inkjet-printed high quality copper acetate films with excellent sensitivity towards H2S. Furthermore, these sensors showed negligible humidity effects and improved selectivity, response time, lower limit of detection and coefficient of variation. The lower limit of detection of copper acetate based sensors was further improved to sub-ppm level by incorporation of catalytic gold nano-particles and subsequent plasma treatment of the sensing film. These sensors were further integrated in an inexpensive wirelessly readable RLC-circuit (where R is resistor, L is inductor and C is capacitor). The performance of these sensors towards biogenic H2S produced during the spoilage of poultry meat in the modified atmosphere package was also demonstrated in this thesis. This serves as a proof of concept that these sensors can be utilized in real life applications.