Problems for satellite centers in obtaining ethical clearance.

Tension-type headache (TTH) is a very common primary headache disorder, with important costs for both patients and society. Often these patients are not willing to take prophylactic medications and resort to complementary therapies. Osteopathic manipulative treatment (OMT) is an interesting option in such field, since it is characterized by a low profile of side effects.

In this study the investigators will assess the efficacy of OMT (semi-structured evaluation and "black box" treatment) in frequent Episodic TTH (ETTH) in an outpatient setting. Preliminary data for power calculation are already available (Rolle et al. 2014), and the investigators plan to recruit 264 ETHH patients by a multicentric, randomized, double-blind, sham-controlled design.

Background:

Primary headache disorders are very common throughout the world, producing widespread and substantial disability and representing a concrete public-health priority. Tension-type headache (TTH) is the most common type of primary headache disorder, with a lifetime prevalence in the general population ranging between 30% and 78% in different studies. In general, headache is a chronic disorder with episodic manifestations that may range from few attacks/year up to daily episodes. Its impact on individuals' lives is greater than has generally been realized, including psychiatric, psychological and social correlates. The impact on patients can be very high, including ictal symptom burden, interictal burden, cumulative burden and impact on other people. The individual burden of TTH includes both symptoms occurring during the attacks (pain, eventually accompanied by no more than one of phonophobia or photophobia, according to International Classification of Headache Disorders) and elements of interictal burden, such as anxiety, mood disorders, affective distress and avoidance behavior. While present, symptoms may cause debility and prostration, and reduce functional ability. Even if patients with TTH generally are not unable to work, effectiveness and productivity may be consistently reduced. This secondary disability is quite significant because headache in general is most common in people between their teens and 50-60 years of age, the productive years. The elements of interictal burden, instead, may continuously affect wellbeing and impair quality of life. Moreover, TTH has a substantial impact on the health system, due to both direct and indirect financial cost. The high prevalence of TTH, considering its individual impact and huge financial costs, has important implications for health policy, since it is a source of high but potentially reducible socioeconomic burden. Essentially, TTH management is a public-health priority.

On the clinical side, tension-type headache has been defined as a multifactorial disorder, conceivably implying the need for tailored treatment strategies. Headache-related disability can usually be reduced by identifying and avoiding triggers combined with pharmacologic and non-pharmacologic treatment (such as relaxation and stress management techniques or physical therapies), but effective treatment modalities are still lacking. Particularly, symptomatic drugs are effective for episodes of TTH, whereas preventive treatment (indicated for frequent and chronic TTH) is, on average, barely effective, and do not display good tolerability. Patients are turning to complementary or alternative therapies for headaches, including osteopathic manipulative therapy (OMTh). One previous pilot study carried out by the investigators has suggested an efficacy for OMTh in frequent episodic TTH, that might represent an alternative treatment strategy to prophylactic drugs. Frequent episodic TTH (ETTH) was chosen for this study since it is the most common diagnostic category with indications for prophylactic drug management. To date there is no rigorously tested evidence that manual therapies in general have a positive effect on TTH, as many reviewers have found. Conflicting results in previous studies might be due both to the low number of clinical trials and an indiscriminate application of different techniques. Some studies, however, have demonstrated positive effects of manipulative therapy.

A systematic review found spinal manipulative therapy as effective as commonly used first-line prophylactic medications for both TTH and migraine headaches, but the Authors emphasized that their conclusions were based on only a few trials, raising the question of whether their analysis was methodologically adequate. A more recent systematic review concluded that spinal manipulation might alleviate TTH but that the small quantity of available data prevented any definitive conclusions. The combination of physical therapies with medications, can also increase the success of the treatment, particularly in case of comorbid mood disorders and unremitting headaches, as previously suggested. Although results of these and others published studies suggest positive effects, OMTh has rarely been rigorously tested for the care of patients with headache in general.

OMTh is not free of costs but is plausibly characterized by fewer contraindications and adverse events than conventional pharmacological treatments, and particularly indicated for patients not compliant with drug regimens and those at increased risk of adverse drug effects. Notably, there is disparity between patient perceptions and clinical definitions of adverse events, as a conceptual model with four inter-related components (expectation, personal investment, osteopathic encounter and clinical change) has suggested. Patients might report mild effects following OMTh and in general all forms of manual therapy, but these effects should not be strictly regarded as adverse events. Our previous pilot trial did not observe adverse events among ETTH patients belonging to both arms of the study (treatment and sham). Exceedingly rare serious adverse events may be observed after spine manipulation, only one of many different techniques usually administered in osteopathic clinical field and recommendations have been already published to meet the requirements of the principles of prevention and precaution. For example, minor unwanted effects of prior manipulation should be searched routinely and taken as contraindication for future spinal manipulations. Great care should be taken when particular anatomic conditions such as cord encroachment or increased vertebra-basilar risk are present. Certainly, besides effectiveness, still to be completely proven, the financial impact of OMTh on subjects and health systems could be also a topic of appraisal for future comparative studies.

However, considering all the exposed priorities in this field, the investigators decided to firstly address in a RCT the question of OMTh efficacy versus OMTh-sham treatment in ETTH.

Aims:

This is a protocol for a randomized controlled trial (RCT) exploring the efficacy of OMTh in ETTH with respect to OMTh-sham treatment by a single blinded multicenter design.

If OMTh effectiveness could be demonstrated in these patients, two putative repercussions in ETTH management might be expected: (a) increased compliance; (b) lower rate of side effects. Furthermore, OMTh would increase the range of available strategies for managing ETTH in clinical practice, perhaps even as an add-on therapy.

Study Design:

This is a multi-centre, double-blinded, randomized, sham-treatment (SHAM)-controlled study using an experimental design.

Presumed ETTH patients will be screened at pre-selected primary care settings (general practitioners), and the diagnosis of TTH reviewed (time -30, or T-30) by a neurologist that will ask patients to complete the headache diary for 30 days before randomization. Diaries will be reviewed at time 0 (T0; baseline) by a blind-rater D.O. that will decide if the number of attacks is compatible with the diagnosis of ETTH, allowing randomization. The blind-rater will perform an osteopathic structural examination that will compulsory include (semi-structured evaluation) also the assessment of temporo-mandibular joint disorders and cervical dysfunctions (TMJD and CD) in order to define putative goals of OMT that will be used for scoring a Goal Attainment Scale (GAS, see below Outcomes) without involving the treating D.O. that will operate independently. Furthermore, patients will be asked to complete the Headache Disability Inventory (HDI) and the Headache Impact Test-6 (HIT-6).

Randomization will be performed by the coordinating centre (Univ. of Milano-Bicocca, Italy) by randomly pre-generated lists; the coordinating centre, without informing the blind-rater, will communicate to the local Osteopathic Clinic these details. Patients will be given instructions to start treatment (OMT vs. SHAM in blind) that will be administered by a treating D.O. unblinded to treatment allocation. Patients will receive 4 weekly treatments completing the headache diary along the whole study (up to T120). The blind-rater will review diaries relative to the each previous period and ask patients to complete the HDI/HIT-6 at 30 days (T30, end of treatment), 60 days (T60, follow-up-1), 90 days (T90, follow-up-2) and 120 days (T120, end of study) with respect to randomization (T0). An osteopathic structural examination will be performed again at T120 (end of study) for GAS scoring. A central database will be filled.

Inclusion criteria will be: (1) a diagnosis of ETTH according to current International Headache Society guidelines; (2) willing to comply with the RCT procedures.

Exclusion criteria will be: (1) patients under 18 or over 65 years of age; (2) use during the previous three months of drugs for acute headache on ten or more days per month; (3) duration of disease less than one year; (4) history of major psychiatric diseases, significant cognitive disorders, significant chronic pain other than headache, or in general from a secondary headache; (5) any kind of ongoing prophylactic treatment or taking place during the whole study period; (6) estroprogestinic therapy started or modified during the whole study period.

Patients will be blindly allocated to (A) an experimental arm (OMT) and (B) a control arm (SHAM), i.e., manual perceptive technique without correction of any observed osteopathic disorder. In order to minimize the perceived differences, both groups will undergo to osteopathic structural examination, with a similar amount of time being spent on each session. OMT will not be protocol-based but the treating D.O. will compulsory have to include the evaluation (and possible treatment) of TMJD and CD (semi-structured treatment). Specifically, OMT will focus on correcting those osteopathic dysfunctions found during the initial evaluation; both structural (including myofascial release and HVLA), visceral and craniosacral techniques will be administered as appropriate. As regards the sham treatment, the operator will be restricted to the assessment of the cranial rhythmic impulse (CRI) in patients, spending a similar amount of time to that being spent on OMT-treated patients.

Primary outcome will be the change at T120 in patient-reported headache frequency of at least 30% with respect to the control group (based on the previous pilot study, Rolle et al. 2014). Secondary outcomes will include: (a) any significant reduction over time or with respect to the control group of the average headache intensity based on a scale between 0 (absence of pain) and 5 (worst perceived pain) (considered more sensible with respect to a 0-to-3 scale, see Rolle et al. 2014); (b) any significant reduction over time or with respect to the control group of the over-the-counter medication usage; (c) any significant reduction over time or with respect to the control group of the HDI/HIT-6 scores; (d) any significant reduction over time or with respect to the control group in patient-reported headache frequency. Tertiary outcome will be: any significant reduction over time or with respect to the control group of the blind-rater evaluation of the osteopathic effects of the whole treatment with respect to the attainments he initially proposed. This score will be assessed purely in terms of correction of those osteopathic dysfunctions that were detected at T0, by using the GAS, with a five-point score ranging from: -2 (much less than expected outcome), to -1 (less than expected outcome), to 0 (expected outcome reached), to +1 (greater than expected outcome), to +2 (much greater than expected outcome).

Finally, side effects will be recorded at each visit. Patients will be instructed to immediately report serious adverse effects.

Inclusion Criteria:

• age ≥18 and ≤65 years-old,
• diagnosis of frequent episodic tension-type headache according to the International Headache Society guidelines,
• frequency of attacks ≥3/month,
• willing to adhere to study procedures,
• signed informed consent

Exclusion Criteria:

• age <18 or >65 years-old,
• headache duration less than one year,
• history of: major psychiatric disorders, relevant cognitive deficits, chronic pain other than headache, secondary headaches,
• any type of headache prophylactic treatment ongoing or started during the study,
• hormonal therapy started or modified during the study,
• participating to other clinical trials,
• not willing to sign informed consent