Pilot Trial of Osteopathic Manipulative Therapy for Patients With Frequent Episodic Tension-Type Headache

Transcription

1 Pilot Tril of Osteopthic Mnipultive Therpy for Ptients With Frequent Episodic Tension-Type Hedche Guido Rolle, MD, DO (Itly); Lucio Tremolizzo, MD, PhD; Frncesco Somlvico, MS; Crlo Ferrrese, MD, PhD; nd Livio C. Bressn, MD From the Itlin School of Osteopthy nd Mnul Therpies (SIOTEMA) in Srtirn (Dr Rolle); the Neurology Unit t the University of Milno-Bicocc in Monz (Drs Tremolizzo nd Ferrrese); Alph Serch in Miln (Mr Somlvico); nd Istituti Clinici di Perfezionmento in Miln (Dr Bressn), Itly. Finncil Disclosures: None reported. Support: None reported. Address correspondence to Guido Rolle, MD, DO (Itly), vi Tsso 8/, Clolziocorte (LC), Itly. E-mil: guidorolle@libero.it Submitted July 15, 2013; finl revision received Februry 11, 2014; ccepted Mrch 10, Context: Osteopthic mnipultive therpy (OMTh; mnipultive cre provided by foreign-trined osteopths) my be used for mnging hedche pin nd relted disbility, but there is need for high-qulity rndomized controlled trils to ssess the effectiveness of this intervention. Objective: To explore the efficcy of OMTh for pin mngement in frequent episodic tension-type hedche (TTH). Design: Single-blind rndomized plcebo-controlled pilot study. Setting: Ptients were recruited from 5 primry cre settings. Ptients: Forty-four ptients who were ffected by frequent episodic TTH nd not tking ny drugs for prophylctic mngement of episodic TTH were recruited. Interventions: Ptients were rndomly llocted to n experimentl or control group. The experimentl group received corrective OMTh techniques, tilored for ech ptient; the control group received ssessment of the crnil rhythmic impulse (shm therpy). The study included 1-month bseline period, 1-month tretment period, nd 3-month follow-up period. Min Outcome Mesures: The primry outcome ws the chnge in ptient-reported hedche frequency, nd secondry outcomes included chnges in hedche pin intensity (discrete score, 1 [lowest perceived pin] to 5 [worst perceived pin]), overthe-counter mediction use, nd Hedche Disbility Inventory score. Results: Forty ptients completed the study (OMTh, n=21; control, n=19). The OMTh group hd significnt reduction in hedche frequency over time tht persisted 1 month (pproximte reduction, 40%; P<.001) nd 3 months (pproximte reduction, 50%; P<.001) fter the end of tretment. Moreover, there ws n bsolute difference between the 2 tretment groups t the end of the study, with 33% lower frequency of hedche in the OMTh group (P<.001). Conclusion: This fesibility study demonstrted the efficcy of OMTh in the mngement of frequent episodic TTH, compred with shm therpy in control group. Osteopthic mnipultive therpy my be preferred over other tretment modlities nd my benefit ptients who hve dverse effects to medictions or who hve difficulty complying with phrmcologic regimens. This protocol my serve s model for future studies. J Am Osteopth Assoc. 2014;114(9): doi: /jo The Journl of the Americn Osteopthic Assocition September 2014 Vol 114 No.9

2 Tension-type hedche (TTH) is prevlent condition with substntil socioeconomic impct, nd the prevlence of frequent episodic TTH my be s high s 24% to 38.3%. 1-3 Tension-type hedche hs been defined s multifctorl disorder, conceivbly implying the need for diversified tretment strtegies. 4 Hedche-relted disbility cn usully be reduced by identifying nd voiding triggers combined with nonphrmcologic nd phrmcologic tretments, but effective tretment modlities re still lcking. 4 Ptients re turning to complementry or lterntive therpies for hedches, including osteopthic mnipultive therpy (OMTh; mnipultive cre provided by foreign-trined osteopths). In prticulr, our necdotl clinicl observtions suggest tht OMTh my hve prophylctic effect in ptients with TTH. An importnt difference between conventionl prophylctic mngement nd OMTh is tht the ltter is not dministered ccording to defined protocols but rther is usully personlized, with techniques tilored to the needs of ech ptient. Perhps prtly for these resons, mny reviewers hve found no rigorously tested evidence tht mnul therpies in generl hve positive effect on TTH. 5-9 Some studies, however, hve demonstrted positive effects of mnipultive therpy. For exmple, Jull et l 10 found tht nonosteopthic mnipultive therpy reduced the symptoms of cervicogenic hedche. A systemtic review by Bronfort et l 11 found spinl mnipultive therpy to be s effective s commonly used first-line prophylctic medictions for both TTH nd migrine hedches, but the uthors emphsized tht their conclusions were bsed on only few trils, rising the question of whether their nlysis ws methodologiclly dequte. Authors of more recent systemtic review 12 concluded tht spinl mnipultion might llevite TTH but tht the smll quntity of vilble dt prevented ny definitive conclusions. On the other hnd, to our knowledge, OMTh hs rrely been rigorously tested for the cre of ptients with hedche, lthough results of some published studies suggest positive effects Thus, there is need for further reserch with high-qulity rndomized controlled trils to rigorously ssess the effectiveness of OMTh vs plcebo in hedche disorders, including TTH. 5,10,17 Considering the costs of TTH mngement, 18,19 the impct of OMTh on mngement cost could lso be tested in future studies. Our objective for the present study ws to perform methodologiclly rigorous pilot rndomized controlled tril evluting the efficcy of OMTh for pin mngement in frequent episodic TTH. If its effectiveness could be demonstrted, we believed tht OMTh, being potentilly chrcterized by fewer contrindictions nd dverse effects thn conventionl tretment, might be good lterntive tretment option, especilly in ptients not complint with mediction regimens nd those with contrindictions to prophylctic medictions. We focused on frequent episodic TTH becuse it is the most common dignostic ctegory with indictions for prophylctic drug mngement. Methods Study Design nd Tretment Alloction The present study ws single-blind rndomized plcebo-controlled pilot study using n experimentl design. Ptients with hedche were screened nd recruited from 5 primry cre settings (generl prctitioners), s indicted in the guidelines for controlled trils of drugs in tension-type hedche. 20 After protocol pprovl, prticipnts received written explntions regrding the objective of the study nd gve their consent regrding sensible dt use. Generl prctitioners received written explntion of the study ims. Inclusion criterion ws dignosis of frequent episodic TTH (we used the episodic TTH dignostic criteri of the Interntionl Clssifiction of Hedche Disorders). 21 The exclusion criteri were ge younger thn 18 or older thn 65 yers; use of drugs for cute hedche on 10 or more dys per The Journl of the Americn Osteopthic Assocition September 2014 Vol 114 No

3 month during the previous 3 months; durtion of disese less thn 1 yer; presence of mjor psychitric diseses; presence of hedche s result of nother disorder (ie, secondry hedche), including cognitive disorders nd chronic pin; or ny kind of ongoing prophylctic mngement during the study period. The study included 1-month bseline period, 1-month tretment period, nd 3-month follow-up period (Figure 1). At the end of the bseline period, ptients were rndomly ssigned to either control or n experimentl group, bsed on coin toss by the treting physicin (G.R.). During the 4 weekly tretment sessions, ptients in the OMTh group received corrective OMTh techniques. Ptients in the control group received ssessment of their crnil rhythmic impulse (shm therpy), considered s plcebo; mnul techniques were used, but observed osteopthic disorders were not corrected. Both OMTh nd shm therpy were provided by the sme physicin (G.R.). To minimize the perceived differences between tretments, ptients in both groups first provided their medicl history, underwent posturl evlution nd osteopthic structurl exmintion, nd were given dvice bout physicl ctivity nd lifestyle, with similr mounts of time spent in both groups. At the end of the ctive tretment period, ptients in both groups were followed up nd evluted fter 1 nd 3 months. Recruitment strted in October 2009 nd finished in April 2010, nd the follow-up of the lst recruited ptients ws completed in August Becuse this study ws explortory (ie, pilot study), no power nlysis ws performed. The guidelines recommend double-blind trils, 20 but mnul techniques cnnot be dministered without the opertor s wreness, so the treting physicin cnnot be blinded. 22 Ptients were blinded, however; in the preliminry document for informed consent, recruited ptients were told tht they would be rndomly ssigned to 1 of 2 groups in which 2 different mnul tretments would be dministered. The corrective techniques pplied in the OMTh group were not protocol bsed 22 but rther were individully tilored for ech ptient, ccording to Greenmn s descriptions. 23 Briefly, the OMTh techniques were focused on correcting osteopthic dysfunctions found during the initil evlution; structurl (including myofscil relese nd highvelocity, low-mplitude), viscerl, nd crnioscrl techniques were performed s pproprite. For the shm therpy, the opertor ws restricted to ssessing the ptient s crnil rhythmic impulse, spending similr mount of time s used for OMTh techniques in the tretment group. Observtion Tretment once weekly Follow-up Follow-up Enrollment 1 mo before bseline Rndomiztion t bseline Outcome ssessment fter 1 mo of tretment Outcome ssessment 1 mo fter tretment Outcome ssessment 3 mo fter tretment Figure 1. Gntt chrt of study of ptients with episodic tension-type hedche. 680 The Journl of the Americn Osteopthic Assocition September 2014 Vol 114 No. 9

4 Tble Bseline Vlues in Ptients Receiving OMTh vs Shm Therpy for Frequent Episodic Tension-Type Hedche (N=40) Bseline Vlue, Men (SE) Vrible OMTh Group (n=21) Control Group (n=19) Frequency, hedches/mo (1.36) 9.58 (0.77) Over-the-counter mediction 8.09 (1.77) 6.63 (1.52) use, medictions/mo Pin intensity score b 2.77 (0.18) 2.44 (0.13) HDI score c 36.6 (2.94) 25.9 (2.57) Bseline vlues were obtined t the end of the 1-month bseline period nd represent vlues for tht month. b Pin intensity ws scored by ptients on scle from 1 (lowest perceived pin) to 5 (worst perceived pin). c Totl possible Hedche Disbility Inventory (HDI) score rnged from 0 (no disbility) to 100 (worst disbility). Abbrevition: OMTh, osteopthic mnipultive therpy. Outcome Mesures Ptients were sked to keep hedche diries, which were used to evlute efficcy of tretment. These diries included chnges in ptient-reported hedche frequency (number of episodes during the period considered), hedche pin intensity (for ech episode during the period, rted from 1 [lowest perceived pin] to 5 [worst perceived pin]), nd over-the-counter mediction use (totl number of medictions used during the period). We lso ssessed hedche-correlted disbility ccording to the Hedche Disbility Inventory (HDI), item survey in which ptients respond to questions relted to disbility s no (0 points), sometimes (2 points), or yes (4 points). The totl possible score for the HDI rnged from 0 (no disbility) to 100 (worst disbility). Hedche frequency ws chosen s the primry outcome. All the other mesures were considered s secondry outcomes. To increse sensitivity to ptient-reported hedche pin intensity, we use scle from 1 to 5 insted of the suggested 0 to 3 scle. 17 The HDI ws selfreported by ptients t the end of the bseline period, t the end of the 30-dy tretment period, nd t the first nd third follow-up month (ie, 1 month nd 3 months fter tretment). The hedche diry referring to ech previous period ws obtined t the sme time points. Sttisticl Anlysis All hypotheses were verified by using the SPSS (version 18) sttistic pckge. All significnce tests were set t P<.05. The sttisticl tests were chosen following verifiction of the normlity distribution of our smples using the Kolmogorov Smirnov test. Chnges over time nd the presence of significnt difference between the 2 study groups were ssessed by the 2-wy nlysis of vrince followed by multiple comprison Tukey test. Ech difference vs bseline for ech ptient (delt) ws ssessed by the 2-tiled unpired t test. Results Sixty-seven ptients were screened, of whom 58 were enrolled (Figure 2). Fourteen dropped out becuse of devition from the protocol 10 owing to poor complince with the study procedures (ie, refusl to dhere to the tretment protocol t the bseline visit) nd the other 4 owing to use of prophylctic drugs during the study The Journl of the Americn Osteopthic Assocition September 2014 Vol 114 No

5 Screened (n=67) Excluded becuse of nondherence to inclusion criteri (n=9) Enrolled (first phse) (n=58) Dropped out owing to protocol devition (n=14) Rndomly ssigned (second phse) (n=44) Allocted to OMTh group (n=21) Allocted to control group (n=23) Dropped out (n=4) Treted per protocol (n=21) Treted per protocol (n=19) Figure 2. Flowchrt of enrollment nd lloction of ptients with episodic tension-type hedche. Abbrevition: OMTh, osteopthic mnipultive therpy. period. Twenty-one ptients were rndomly ssigned to the OMTh group nd 23 to the control group. Four ptients in the control group were eventully excluded from the study (per-protocol nlysis): 2 specificlly sked to interrupt the protocol during ctive tretment, nd the other 2 used prophylctic drugs during follow-up; ll ptients in the OMTh group completed the study. Therefore, totl of 40 ptients completed the study: 21 in the OMTh group nd 19 in the control group (see bseline chrcteristics in the Tble). The OMTh group included 4 mle nd 17 femle ptients, with men (SD) ge of 32.7 (10.8) yers, nd the control group included 2 mle nd 17 femle ptients, with men ge of 36.3 (13.2) yers. No dverse events were recorded throughout the entire study for either group. We found significnt chnge in hedche frequency over time in the OMTh group (n pproximtely 50% reduction vs bseline fter 3 months of follow-up; P<.001) (Figure 3). We lso found n bsolute difference between the 2 groups t 3 months (P<.001), with 33% lower frequency of hedche in the OMTh group. Regrding secondry outcomes, over-the-counter mediction use ws reduced only in the OMTh group, t ll time points fter bseline, compred with the bseline men (resulting in n pproximtely 45% reduction vs bseline fter 3 months of follow-up; P<.001) (Figure 4). Pin intensity ws lso modestly reduced over time in the OMTh group (resulting in n pproximtely 20% reduction vs bseline fter 3 months of follow-up; P<.001). Finlly, the HDI score showed no significnt improvement; however, chnge in the totl score of t lest 29 points from test to retest is required before the vrition cn be ttributed to tretment effects, 22 nd the low bseline HDI score in our smples might help explin the 682 The Journl of the Americn Osteopthic Assocition September 2014 Vol 114 No. 9

6 pprent lck of effect. Therefore, the comprison between the HDI score chnges in the 2 groups highlighted difference over time in the OMTh group (resulting in n pproximtely 40% reduction vs bseline fter 3 months of follow-up; P<.001). Discussion Frequent episodic TTH ws chosen for this tril becuse it is one of the most common indictions for prophylctic mngement, for which we hypothesized tht OMTh might represent n lterntive. The drug tretments vilble for this condition re often unstisfctory, nd the socil nd helth system costs cn be high. 3 The results of our fesibility study suggest tht OMTh my be effective in the mngement of frequent episodic TTH. Hedche frequency in the OMTh group, the primry outcome, ws significntly reduced (by pproximtely 33%) compred with the control group t the end of the study. Secondry outcomes were lso prtilly chieved, in prticulr reduction in use over time of over-thecounter medictions, implying possible reduction in dverse effects nd costs. No dverse effects were reported in this tril, lthough OMTh is not completely free of such effects. 25 The positive effects of OMTh on hedche pin control could be result of specific neurochemicl effects, including n increse in the concentrtion of circulting opioids nd serotonin with the involvement of serotoninergic nd nordrenergic descending trcts. 26 However, the moleculr bses of OMTh clinicl results re mostly unknown, nd further studies re needed to investigte this issue. Trils of OMTh, in prt becuse OMTh techniques re individully tilored to ech ptient s needs, often fil to meet the strict evidence-bsed medicine requirements. In this study, therefore, we tried to pln preliminry rndomized controlled tril tht ws methodologiclly rigorous enough to be used s model for plnning future clinicl trils in ptients with episodic TTH. There is need for future trils with sufficient power nlysis; the present pilot study my offer methodologic reference for designing such trils. Hedches/mo, Men (SE) Bseline End of tretment, 1 mo OMTh group Control group In plnning the study we encountered other methodologic issues. The first concerns the double-blind condition. Unfortuntely, OMTh nd other mnul therpies cnnot be dministered without the opertor s wreness, thereby mking it impossible to perform doubleblind trils. Thus, ll types of mnul interventions my hve n intrinsic limit. 22 In the current study, shm therpy ws used in the control group, llowing mnul pproch tht specificlly excluded the correction of osteopthic dysfunctions. The lck of double blinding ws clerly our study s gretest limittion long with the perprotocol nlysis, which we preferred becuse it is intrinsiclly suited to preliminry nd pilot studies, even though it is n obvious source of ttrition bis. Follow-up, 1 mo The second limittion concerns possible differences between groups in ptient confidence. Ptients my perceive OMTh s more credible tretment thn mny control procedures, nd the study should be designed to equlize ptient perceptions mong interventions. 22 b Follow-up, 3 mo Figure 3. Men hedche frequency of ptients with episodic tension-type hedche in the osteopthic mnipultive therpy (OMTh) nd control groups. P<.001 for difference vs bseline; b P<.001 for difference between groups. Both vlues bsed on 2-wy nlysis of vrince followed by Tukey post hoc nlysis. The Journl of the Americn Osteopthic Assocition September 2014 Vol 114 No

7 A Medictions/mo, Men (SE) B Pin Intensity Score, Men (SE) C 100 HDI Score, Men (SE) Bseline End of tretment, 1 mo OMTh group Control group Follow-up, 1 mo Follow-up, 3 mo Figure 4. (A) Over-the-counter mediction usge, (B) hedche pin intensity scores (scle, 1 [lowest perceived pin] to 5 [worst perceived pin]), nd (C) Hedche Disbility Inventory (HDI) scores (scle, 0-100) of ptients with episodic tension-type hedche in the osteopthic mnipultive therpy (OMTh) nd control groups. P<.001 for difference vs bseline (bsed on 2-wy nlysis of vrince followed by Tukey post hoc nlysis). We therefore tried to mke the control nd tretment interventions nd settings s similr s possible to minimize perceived differences; ptients in both groups provided their medicl history, underwent posturl evlution nd osteopthic structurl exmintion, nd were given dvice bout physicl ctivity nd lifestyle, with similr mounts of time being spent in both groups. The question of wht should be considered n dequte plcebo for OMTh is both relevnt nd complex, nd previous studies, conducted with resonbly robust designs, hve given different nswers. For exmple, in single-blind rndomized experimentl study, 16 OMTh ws offered to ptients with TTH s n dd-on therpy supplementing progressive musculr relxtion performed lone t home. To minimize bis, we decided tht our control group should be ttended to by the opertor for the sme mount of time s our OMTh group nd tht the procedures performed in the 2 groups should be s similr s possible. The third limittion of our tril involves the lck of comprison between the novel intervention (in this cse OMTh) nd the therpeutic criterion stndrd (eg, mitriptyline or other drugs) to ensure sensitivity of the model; such comprison is requested in drug trils of episodic TTH prophylxis. 20 This importnt limittion clerly needs to be ddressed further in subsequent studies with sufficient power. However, prophylctic drug mngement often implies less contct (physicl nd over time) between ptients nd physicins, nd our im ws specificlly to distinguish ny therpeutic effect of OMTh from the simple plcebo effect of more frequent mnul contct. The lst methodologic question concerns OMTh techniques per se. Tretments were individully tilored for ech ptient, s is usully done in osteopthic clinicl prctice, with corrective techniques pplied to ny noted dysfunctions. Becuse clinicl observtions in the field suggest tht stndrdized osteopthic tretments re less effective thn tilored ones, we decided tht preestblished protocol of techniques could limit the efficcy of OMTh; this option might be dopted in future trils, perhps with mixed (prtilly structured) protocols. 684 The Journl of the Americn Osteopthic Assocition September 2014 Vol 114 No. 9

8 Conclusion Considering the results of our fesibility pilot tril, OMTh my be n interesting option for mnging episodic TTH one chrcterized by few contrindictions nd dverse effects nd prticulrly indicted for ptients not complint with drug regimens nd those t incresed risk of dverse drug effects. Author Contributions Drs Rolle nd Tremolizzo provided substntil contributions to conception nd design nd cquisition of dt nd drfted the rticle nd revised it for submission; Dr Somlvico provided substntil contribution to nlysis nd interprettion of dt; nd Drs Ferrrese nd Bressn gve finl pprovl of the version of the rticle to be published. References 1. Rsmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology of hedche in generl popultion prevlence study. J Clin Epidemiol. 1991;44(11): Schwrtz BS, Stewrt WF, Simon D, Lipton RB. Epidemiology of tension-type hedche. JAMA. 1998;279(5): Jensen R, Stovner LJ. Epidemiology nd comorbidity of hedche. Lncet Neurol. 2008;7(4): doi: /s (08) Bendtsen L, Jensen R. Treting tension-type hedche n expert opinion. Expert Opin Phrmcother. 2011;12(7): doi: / Fernández-de-Ls-Peñs C, Alonso-Blnco C, Cudrdo ML, Mingolrr JC, Brrig FJ, Prej JA. Are mnul therpies effective in reducing pin from tension-type hedche? systemtic review. Clin J Pin. 2006;22(3): Fernández-de-Ls-Peñs C, Alonso-Blnco C, Sn-Romn J, Mingolrr-Pge JC. Methodologicl qulity of rndomized controlled trils of spinl mnipultion nd mobiliztion in tension-type hedche, migrine, nd cervicogenic hedche. J Orthop Sports Phys Ther. 2006;36(3): Tso JC. Effectiveness of mssge therpy for chronic, non-mlignnt pin: review. Evid Bsed Complement Alternt Med. 2007;4(2): doi: /ecm/nel Lenssinck ML, Dmen L, Verhgen AP, Berger MY, Psschier J, Koes BW. The effectiveness of physiotherpy nd mnipultion in ptients with tension-type hedche: systemtic review. Pin. 2004;112(3): Astin JA, Ernst E. The effectiveness of spinl mnipultion for the tretment of hedche disorders: systemtic review of rndomized clinicl trils. Cephllgi. 2002;22(8): Jull G, Trott P, Potter H, et l. A rndomized controlled tril of exercise nd mnipultive therpy for cervicogenic hedche. Spine (Phil P 1976). 2002;27: Posdzki P, Ernst E. Spinl mnipultions for tension-type hedches: systemtic review of rndomized controlled trils. Complement Ther Med. 2012;20(4): doi: /j.ctim Hoyt WH, Shffer F, Brd DA, et l. Osteopthic mnipultion in the tretment of muscle-contrction hedche. J Am Osteopth Assoc. 1979;78(5): Ajimsh MS. Effectiveness of direct vs indirect technique myofscil relese in the mngement of tension-type hedche. J Bodyw Mov Ther. 2011;15(4): doi: /j.jbmt Voigt K, Liebnitzky J, Burmeister U, et l. Efficcy of osteopthic mnipultive tretment of femle ptients with migrine: results of rndomized controlled tril. J Altern Complement Med. 2011;17(3): doi: /cm Anderson RE, Seniscl C. A comprison of selected osteopthic tretment nd relxtion for tension-type hedches. Hedche. 2006;46(8): Bronfort G, Nilsson N, Hs M, et l. Non-invsive physicl tretments for chronic/recurrent hedche. Cochrne Dtbse Syst Rev. 2004;(3):CD Lenerts ME. Burden of tension-type hedche. Curr Pin Hedche Rep. 2006;10(6): Stovner Lj, Hgen K, Jensen R, et l. The globl burden of hedche: documenttion of hedche prevlence nd disbility worldwide. Cephllgi. 2007;27(3): Bendtsen L, Bigl ME, Cerbo R, et l. Guidelines for controlled trils of drugs in tension-type hedche: second edition. Cephllgi. 2010;30(1):1-16. doi: /j x. 21. Hedche Clssifiction Committee of the Interntionl Hedche Society. The Interntionl Clssifiction of Hedche Disorders, 3rd edition (bet version). Cephllgi. 2013;33(9): Liccirdone JC, Russo DP. Blinding protocols, tretment credibility, nd expectncy: methodologic issues in clinicl trils of osteopthic mnipultive tretment. J Am Osteopth Assoc. 2006;106(8): Greenmn PE. Principles of Mnul Medicine. 3rd ed. Phildelphi, PA: Lippincott Willims & Wilkins; Jcobson GP, Rmdn NM, Aggrwl SK, Newmn CW. The Henry Ford Hospitl Hedche Disbility Inventory (HDI). Neurology. 1994;44(5): Rjendrn D, Bright P, Bettles S, Crnes D, Mullinger B. Wht puts the dverse in dverse events? ptients perceptions of post-tretment experiences in osteopthy qulittive study using focus groups. Mn Ther. 2012;17(4): doi: /j.mth Degenhrdt BF, Drmni NA, Johnson JC, et l. Role of osteopthic mnipultive tretment in ltering pin biomrkers: pilot study. J Am Osteopth Assoc. 2007;107(9): Americn Osteopthic Assocition 11. Bronfort G, Assendelft WJ, Evns R, Hs M, Bouter L. Efficcy of spinl mnipultion for chronic hedche: systemtic review. J Mnipultive Physiol Ther. 2001;24(7): The Journl of the Americn Osteopthic Assocition September 2014 Vol 114 No