Chiropractic spinal manipulative therapy for acute neck pain: A 4-arm clinical placebo randomized controlled trial. A prospective study protocol.

INTRODUCTION: Neck pain poses enormous individual and societal costs worldwide. Spinal manipulative therapy and Non-Steroidal Anti-Inflammatory Drug treatment are frequently used despite a lack of compelling efficacy data. This protocol describes a multicentre 4-arm, clinical placebo randomized controlled trial (RCT), investigating the efficacy of chiropractic spinal manipulative therapy (CSMT) versus sham CSMT, ibuprofen, and placebo medicine for acute neck pain. This superiority study will employ parallel groups, featuring a 1:1:1:1 allocation ratio. MATERIAL AND METHODS: We will randomize 320 participants equally into four groups: CSMT, sham CSMT, ibuprofen, or placebo medicine. CSMT groups are single-blinded, while the medicine groups are double-blinded. Data will be collected at baseline (Day 0), during treatment and post-treatment. The primary endpoint will assess the difference in mean pain intensity from Day 0 to Day 14 on a numeric rating scale 0-10; the CSMT group is compared to sham CSMT, ibuprofen, and placebo medicine groups, respectively. Secondary endpoints will assess mean pain intensity and mean duration at different time points, and adverse events, blinding success, and treatment satisfaction, including comparison between ibuprofen and placebo medicine. Power calculation is based on a mean neck pain rating of 5 at Day 0, with standard deviation of 1 in all groups. Mean pain reduction at Day 14 is expected to be 60% in the CSMT group, 40% in sham CSMT and ibuprofen groups, and 20% in the placebo medicine group. A linear mixed model will compare the mean values for groups with corresponding 95% confidence intervals. P values below 0.017 will be considered statistically significant. All analyses will be conducted blinded from group allocation. DISCUSSION: This RCT aims towards the highest research standards possible for manual-therapy RCTs owing to its two placebo arms. If CSMT and/or ibuprofen proves to be effective, it will provide evidence-based support for CSMT and/or ibuprofen for acute neck pain. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05374057. EU Clinical Trials Register: EudraCT number: 2021-005483-21.

Spinal Manipulative Therapy for Acute Neck Pain: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

(1) Background: Acute neck pain is common and usually managed by medication and/or manual therapy. General practitioners (GPs) hesitate to refer to manual therapy due to uncertainty about the effectiveness and adverse events (AEs); (2) Method: To review original randomized controlled trials (RCTs) assessing the effect of spinal manipulative therapy (SMT) for acute neck pain. Data extraction was done in duplicate and formulated in tables. Quality and evidence were assessed using the Cochrane Back and Neck (CBN) Risk of Bias tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria, respectively; (3) Results: Six studies were included. The overall pooled effect size for neck pain was very large -1.37 (95% CI, -2.41, -0.34), favouring treatments with SMT compared with controls. A single study that showed that SMT was statistically significantly better than medicine (30 mg ketorolac im.) one day post-treatment, ((-2.8 (46%) (95% CI, -2.1, -3.4) vs. -1.7 (30%) (95% CI, -1.1, -2.3), respectively; p = 0.02)). Minor transient AEs reported included increased pain and headache, while no serious AEs were reported; (4) Conclusions: SMT alone or in combination with other modalities was effective for patients with acute neck pain. However, limited quantity and quality, pragmatic design, and high heterogeneity limit our findings.

Effect of oral and transdermal oestrogen therapy on bone mineral density in functional hypothalamic amenorrhoea: a systematic review and meta-analysis.

BACKGROUND: Female athletes might develop reduced bone mineral density (BMD) and amenorrhoea due to low energy intake. OBJECTIVE: To systematically review the literature of randomised controlled trials (RCTs) assessing the effect of oestrogen oral contraceptives (OCP), conjugated oestrogens (CE) and transdermal estradiol (TE) on BMD in premenopausal women with functional hypothalamic amenorrhoea (FHA) due to weight loss, vigorous exercise and/or stress. METHODS: A comprehensive literature search in PubMed, MEDLINE, Cochrane Library, Ovid and CINAHL from inception to 1 October 2020. DATA EXTRACTION AND SYNTHESIS: Two authors independently extracted data. When possible, the data were pooled in a random-effects meta-analysis. MAIN OUTCOMES: Difference in BMD (g/cm2) at the lumbar spine. RESULTS: Nine RCTs comprising 770 participants met the inclusion criteria; five studies applied OCP, two CE and two TE. Four RCTs (two OCP, two TE) found an increased BMD in premenopausal women with FHA, and five (three OCP, two CE) found a decreased BMD compared with controls. A meta-analysis showed no difference in BMD between the treatment and control groups, (standardised mean difference (SMD) 0.30, 95% CI -0.12 to 0.73). A secondary analysis for change scores from baseline to first assessment point, showed a similar overall result (SMD 0.17, 95% CI -0.16 to 0.51). No serious adverse events were reported. CONCLUSION: The literature suggests that TE might increase lumbar BMD in premenopausal women with FHA, but pooled results revealed no effect of the intervention. The findings do not support oestrogen therapy to improve BMD in these patient groups.

Validity of self-reported assessment of Severity of Dependence Scale in Medication-Overuse Headache.

The interview-based Severity of Dependence Scale (SDS) predicts the outcome of withdrawal therapy in Medication-Overuse Headache (MOH). We aimed to compare the interview-based SDS with a self-administrated written version. Fifty-three MOH patients, 19 chronic headache patients without medication overuse and 25 population controls were recruited from a previous randomized controlled trial. The SDS was scored in a telephone interview by headache experts, further, the participants filled in the SDS as a part of a self-administered questionnaire. The SDS assesses scores dependence through five questions, each scored from 0 to 3. A score of ≥5 is associated with MOH. Mean SDS scores were 2.8 (SD 3.0) vs. 3.1 (SD 2.9), p = 0.12, for the interview vs. the self-reported questionnaire, with a correlation 0.78. There was a non-significant bias of 0.32 (95% limits of agreement of -3.6; 4.2) between the two methods in the Bland-Altman analysis. A self-reported SDS questionnaire can be used, and may yield valuable information as a screening tool prior to headache consultations or studies. The possibilities of designing web-based self-treatment tools based on SDS self-assessment and brief intervention may be a future approach for a large group of patients.

Epidemiology and management of medication-overuse headache in the general population.

Medication-overuse headache is a worldwide challenge as it affects 1-2% of the general population. Some people are more prone to medication overuse, which can be ascertained by applying five simple questions about dependence. Detoxification of the overused medication is a cheap and effective treatment strategy. A short advice seems to be sufficient for people from the general population whom seek their general practitioner. Treatment is often more complicated in neurologist and hospital settings, most likely due to a combination of treatment failure in general practice and co-morbidity of other disorders including different types of headaches.

A risk-benefit assessment strategy to exclude cervical artery dissection in spinal manual-therapy: a comprehensive review.

Cervical artery dissection refers to a tear in the internal carotid or the vertebral artery that results in an intramural haematoma and/or an aneurysmal dilatation. Although cervical artery dissection is thought to occur spontaneously, physical trauma to the neck, especially hyperextension and rotation, has been reported as a trigger. Headache and/or neck pain is the most common initial symptom of cervical artery dissection. Other symptoms include Horner's syndrome and lower cranial nerve palsy. Both headache and/or neck pain are common symptoms and leading causes of disability, while cervical artery dissection is rare. Patients often consult their general practitioner for headache and/or neck pain, and because manual-therapy interventions can alleviate headache and/or neck pain, many patients seek manual therapists, such as chiropractors and physiotherapists. Cervical mobilization and manipulation are two interventions that manual therapists use. Both interventions have been suspected of being able to trigger cervical artery dissection as an adverse event. The aim of this review is to provide an updated step-by-step risk-benefit assessment strategy regarding manual therapy and to provide tools for clinicians to exclude cervical artery dissection. Key messages Cervical mobilization and/or manipulation have been suspected to be able to trigger cervical artery dissection (CAD). However, these assumptions are based on case studies which are unable to established direct causality. The concern relates to the chicken and the egg discussion, i.e. whether the CAD symptoms lead the patient to seek cervical manual-therapy or whether the cervical manual-therapy provoked CAD along with the non-CAD presenting complaint. Thus, instead of proving a nearly impossible causality hypothesis, this study provide clinicians with an updated step-by-step risk-benefit assessment strategy tool to (a) facilitate clinicians understanding of CAD, (b) appraise the risk and applicability of cervical manual-therapy, and (c) provide clinicians with adequate tools to better detect and exclude CAD in clinical settings.

Severity of Analgesic Dependence and Medication-overuse Headache.

BACKGROUND AND AIMS: Medication-overuse headache (MOH) is a common chronic headache caused by overuse of headache analgesics. It has similarities with substance dependence disorders. The treatment of choice for MOH is withdrawal of the offending analgesics. Behavioral brief intervention treatment using methods adapted from substance misuse settings is effective. Here we investigate the severity of analgesics dependence in MOH using the Severity of Dependence Scale (SDS), validate the SDS score against formal substance dependence diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and examine whether the SDS predicts successful withdrawal. METHODS: Representative recruitment from the general population; 60 MOH patients, 15 chronic headache patients without medication overuse and 25 population controls. Headaches were diagnosed using the International Classification of Headache Disorders, medication use was assessed and substance dependence classified according to the DSM-IV. The SDS was scored by interviewers blinded to patient group. Descriptive statistics were used and validity of the SDS score assessed against a substance dependence diagnosis using ROC analysis. RESULTS: Sixty-two percent of MOH patients overused simple analgesics, 38% centrally acting analgesics (codeine, opiates, triptans). Fifty percent of MOH patients were classified as DSM-IV substance dependent. Centrally active medication and high SDS scores were associated with higher proportions of dependence. ROC analysis showed SDS scores accurately identified dependence (area under curve 88%). Lower SDS scores were associated with successful withdrawal (P = 0.004). CONCLUSIONS: MOH has characteristics of substance dependence which should be taken into account when choosing treatment strategy. TRIAL REGISTRATION: Based on data collected in previously reported randomized BIMOH trial (; in the present manuscript, Clinical trials registration number: NCT01314768). The present part, however, represents observational data and is not a treatment trial.

Impact of chronic headache on workdays, unemployment and disutility in the general population.

BACKGROUND: Data on the socioeconomic burden of chronic headache (≥15 days/last month or >180 days/year) is lacking. This study investigated the impact of chronic headache on sickness absence, unemployment and disutility in the general population in Norway. METHODS: 30 000 persons aged 30-44 from the general population were screened for chronic headache by a screening questionnaire. The responder rate was 71%. The International Classification of Headache Disorders was used. We analysed the association of chronic headache with lost workdays, days with ≥50% reduced productivity, sick leave, unemployment and disutility, as assessed with the Short-Form Six-Dimension (SF-6D) in separate regression analyses. RESULTS: Eighty-three per cent (427/516, 79% women) of the eligible participants completed the data on workdays and utility. They reported a mean of 9.7 (SD 24.8) workdays lost over the last 3 months, because of headache. The mean disutility score (1-SF-6D score) was 0.41. Thirty-three per cent were on long-term (>1 year) sick leave. The OR for being on sick leave was 1.9 (95% CI 1.1 to 3.2, p=0.017) for those with secondary compared with primary chronic headache. Similarly, the OR for increased number of workdays lost to headache was 3.5 (95% CI 1.8 to 6.5, p<0.001) and for unemployment 1.7 (95% CI 1.0 to 2.9, p=0.07), for those with secondary compared with primary chronic headache. Secondary chronic headache, high headache frequency and high psychological distress were significantly associated with higher disutility score. CONCLUSIONS: The burden of chronic headache in the general population is substantial with high rates of lost workdays and disutility.

Illness perception in people with primary and secondary chronic headache in the general population.

BACKGROUND: Chronic headache (headache ≥15 days/month) is a leading cause of disability. Illness perception, beliefs and cognitive models are likely central for patient understanding of their chronic pain condition and are associated with treatment outcome. However, these factors are insufficiently described in chronic headache. OBJECTIVE: To describe illness perception, and to explore the effect of background variables and headache characteristics on illness perceptions in primary and secondary chronic headaches in the general population. METHODS: 30,000 persons aged 3044 from the general population were screened for chronic headache by a mailed questionnaire. Those with self-reported chronic headache were interviewed by headache specialists. The questionnaire response rate was 71%, and the interview participation rate was 74%. The International Classification of Headache Disorders III was applied. Illness perception was assessed by the Revised Illness Perception Questionnaire (IPQ-R). The statistical approach was exploratory. RESULTS: 405 of the 516 eligible participants (78%) completed the IPQ-R. Confirmatory factor analysis showed good internal validity in chronic headache. People believed their chronic headache to be long-lasting, with negative life consequences including emotional distress. Severe headache-related disability was associated with more perception of chronicity, more perceived consequences, emotional load and illness identity and less illness coherence. People with secondary chronic headache scored significantly higher on chronicity and life consequences, and had less personal control than those with primary chronic headache. CONCLUSION: Chronic primary and secondary headache is associated with a high symptom burden and chronicity with large perceived negative consequences for daily living, suggesting multidisciplinary management may be necessary.

Symptoms of premenstrual syndrome in female migraineurs with and without menstrual migraine.

BACKGROUND: Menstrual migraine (MM) and premenstrual syndrome (PMS) are two conditions linked to specific phases of the menstrual cycle. The exact pathophysiological mechanisms are not fully understood, but both conditions are hypothesized to be triggered by female sex hormones. Co-occurrence of MM and PMS is controversial. The objective of this population-based study was to compare self-assessed symptoms of PMS in female migraineurs with and without MM. A total of 237 women from the general population who self-reported migraine in at least50% of their menstruations in a screening questionnaire were invited to a clinical interview and diagnosed by a neurologist according to the International Classification of Headache Disorders II (ICHD II), including the appendix criteria for MM. All women were asked to complete a self-administered form containing 11 questions about PMS-symptoms adapted from the Diagnostic and Statistical Manual of Mental Disorders. The number of PMS symptoms was compared among migraineurs with and without MM. In addition, each participant completed the Headache Impact test (HIT-6) and Migraine Disability Assessment Score (MIDAS). FINDINGS: A total of 193 women returned a complete PMS questionnaire, of which 67 women were excluded from the analyses due to current use of hormonal contraception (n = 61) or because they did not fulfil the ICHD-criteria for migraine (n = 6). Among the remaining 126 migraineurs, 78 had MM and 48 non-menstrually related migraine. PMS symptoms were equally frequent in migraineurs with and without MM (5.4 vs. 5.9, p = 0.84). Women with MM reported more migraine days/month, longer lasting migraine attacks and higher HIT-6 scores than those without MM, but MIDAS scores were similar. CONCLUSION: We did not find any difference in number of self-reported PMS-symptoms between migraineurs with and without MM.

Psychological distress, neuroticism and disability associated with secondary chronic headache in the general population - the Akershus study of chronic headache.

BACKGROUND: Primary headaches are associated with psychological distress, neuroticism and disability. However, little is known about headache-related disability and psychological distress among people with secondary chronic headaches. METHODS: 30,000 persons aged 30-44 from the general population was screened for headache by a questionnaire. The responder rate was 71%. The International Classification of Headache Disorders with supplementary definitions for chronic rhinosinusitis and cervicogenic headache were used. The Hopkins Symptom Checklist-25 assessed high psychological distress, the Migraine Disability Assessment questionnaire assessed disability, and Eysenck Personality Questionnaire assessed neuroticism. RESULTS: Ninety-five of the 113 eligible participants (84%) completed the self-reported questionnaire. A total of 38 people had chronic post-traumatic headache, 21 had cervicogenic headache, and 39 had headache attributed to chronic rhinosinusitis, while 9 had co-occurrence of chronic post-traumatic and cervicogenic headache. Six persons had miscellaneous secondary chronic headaches. Overall, 49% of those with secondary chronic headache reported high psychological distress, which is significantly higher than in the general population. A high level of neuroticism was significantly more common in those with secondary chronic headache than in the general population. Severe headache-related disability was reported by 69%. 92 persons were followed up after 3 years. A low headache frequency was the only significant predictor of improvement of ≥ 25% in headache days. Having post-traumatic or cervicogenic headache and not headache attributed to chronic rhinosinusitis predicted an increased risk > 25% worsening of headache days or having a severe disability at 3 years follow-up. CONCLUSION: Psychological distress and neuroticism were more common among people with secondary chronic headache than in the general population. Only a high headache frequency was significantly associated with increased headache disability at baseline and a poor prognosis in the long term.

Excessive daytime sleepiness in chronic migraine and chronic tension-type headache from the general population.

Introduction A relationship between headache and excessive daytime sleepiness (EDS) has been suggested. This study investigated this association in relation to people with chronic migraine or chronic tension-type headaches. Methods A total of 30,000 persons aged 30-44 from the general population were screened for chronic headache. Those eligible were interviewed by a headache specialist. EDS was defined as Epworth sleepiness scale score >10. Logistic regression models were used. Results Among the 323 eligible participants, 21.1% had EDS. In multivariable logistic regression analysis, the odds ratios (OR) of EDS were not significantly different in people with CM and CTTH. However, high headache frequency was associated with EDS (OR 2.03 (95% CI 1.11-3.73, p = 0.022)) for those with ≥ 80 compared to < 80 headache days/3 months, after adjustment for type of headache, age, and gender. Conclusions Increased EDS was associated with higher headache frequency, but not with specific headache diagnoses.

Excessive daytime sleepiness in secondary chronic headache from the general population.

BACKGROUND: Excessive daytime sleepiness (EDS, defined as Epworth sleepiness scale score > 10) is a common symptom, with a prevalence of 10-20% in the general population. It is associated with headache and other chronic pain disorders. However, little is known about the prevalence of EDS among people with secondary chronic headaches. FINDINGS: A total of 30,000 persons aged 30-44 from the general population was screened for headache by a questionnaire. The 633 eligible participants with self-reported chronic headache were interviewed and examined by a headache specialist who applied the International Classification of Headache Disorders with supplementary definitions for chronic rhinosinusitis and cervicogenic headache. A total of 93 participants had secondary chronic headache and completed the ESS. A total of 47 participants had chronic post-traumatic headache (CPTH) and/or cervicogenic headache (CEH), 39 participants had headache attributed to chronic rhinosinusitis (HACRS), while 7 had other secondary headaches. 23.3% of those with CPTH, CEH or HACRS reported EDS. In multivariable logistic regression analysis the odds ratios of EDS were not significantly different in people with CPTH/CEH or HACRS. CONCLUSION: Almost one out of four subjects with secondary chronic headache reported EDS with no differences between the various secondary chronic headaches.

Chiropractic spinal manipulative therapy for cervicogenic headache: a single-blinded, placebo, randomized controlled trial.

OBJECTIVE: Cervicogenic headache is a disabling headache where pharmacological management have limited effect. Thus, non-pharmacological management is warranted. Our objective was therefore to investigate the efficacy of chiropractic spinal manipulative therapy versus placebo (sham manipulation) and control (continued usual but non-manual management) for cervicogenic headache in a prospective 3-armed single-blinded, placebo, randomized controlled trial of 17 months' duration. RESULTS: Nineteen participants were equally randomized into the three groups, and 12 participants completed the randomized controlled trial. Headache frequency improved at all time points in the chiropractic spinal manipulative therapy and the placebo group. Headache index improved in the chiropractic spinal manipulative therapy group at all time points, while it improved at 6 and 12 months' follow-up in the placebo group. The control group remained unchanged during the whole study period. Adverse events were few, mild and transient. Blinding was concealed throughout the RCT. Thus, our results suggest that manual-therapy might be a safe treatment option for participants with cervicogenic headache, but data need to be confirmed in a randomized controlled trial with sufficient sample size and statistical power. Trial registration ClinicalTrials.gov identifier: NCT01687881, 11 September 2012.