The Use of Methylsulfonylmethane (MSM) in the Treatment of Low Back Pain.
Phase: PHASE3
Conditions: Low Back Pain
Sponsor: Mike O'Callaghan Military Hospital

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Document Date: 4/5/2018 
The use of Methylsulfonylmethane (MSM) in the treatment of low back pain. 
NCT02268305 

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Non-Exempt Human Research Study 
PROTOCOL FOR CLINICAL INVESTIGATION – NON-EXEMPT HUMAN 
(Wilford Hall Ambulatory Surgical Center – WHASC) 
 
PROTOCOL SUMMARY 
1.  Title: 
The use of Methylsulfonylmethane (MSM) in the treatment of low back pain. 
FWH20140075H 
 
2.0.  Principal Investigator (PI): 
 
                              NELLIS AFB PI: 
 
        
Name 
 
Paul Crawford 
Rank/Corps or Civilian Rating 
 
Col, USAF, MC 
Date of IRB Approved CITI Training & 
Date of Good Clinical Practice Training  
12/28/2017 
Branch of Service 
USAF 
AD Mil/DoD Civilian/Ctr/Non-DoD Civ 
AD 
Department  & Base 
 
Department of Medical Education, Nellis AFB 
Phone & Pager #  
(702) 653-3298 
E-Mail Address & AKO/DKO E-Mail Address 
Paul.F.Crawford.mil@mail.mil 
 
3.0.  Research Plan: 
 
3.1. Purpose:  
The purpose of this study is to assess whether Methylsulfonylmethane (MSM) plus standard of care naproxen improves 
symptoms of lower back pain versus standard of care naproxen plus placebo. 
 
3.2. Hypotheses, Research Questions or Objectives:  
Does the addition of MSM to standard of care treatment improve symptoms of lower back pain assessed by the Roland-Morris 
Disability Questionnaire (RMDQ) and Pain Impact Questionnaire (PIQ-6)? 
 
4.  Brief Summary of the study:  
We are studying whether MSM plus standard of care naproxen improves symptoms of lower back pain compared to standard of 
care naproxen plus placebo. Subjects will be randomized into 1 of 2 groups. Group 1 will take by mouth 6000 milligrams (mgs) of 
MSM plus standard of care naproxen. Group 2 will take by mouth placebo capsules plus standard of care naproxen. Subjects will 
be instructed to take their study pills for 12 weeks and record on a study diary. They will then be followed up for one final visit 4 
weeks later. RMDQ, PIQ-6, pain level, comprehensive metabolic panel (CMP), complete blood count (CBC) will be assessed at 4 
week intervals for 12 weeks. Subjects’ participation will last 16 weeks. 
 
5. Subjects:  
We will recruit male and female NELLIS AFB DoD beneficiaries between the ages of 18-65 years old with symptoms of lower back 
pain from the any of the clinics at the Mike O’Callaghan Military Medical Center at Nellis Air Force Base.  Some subjects may be 
the patients of the PI or AI; however, the PI will have the AI, or Study staffs recruit their patients to prevent any misconception 
of coercion. No special populations (i.e. children, prisoners, pregnant women, mentally disabled persons, or economically or 
educationally disadvantaged persons) will be eligible for this study. 
 
6. Inclusion/exclusion criteria:  
• 
Inclusion: 
o 
DoD beneficiaries between the ages of 18-65 years old. 
o 
Symptoms of Low Back Pain greater than 12 weeks duration. 
o 
Patients with a history of lower back surgery may be included. 
• 
Exclusion: 
o 
DoD beneficiaries less than 18 years old or greater than 65 years old. 
o 
Lower back pain caused by any of the following: 
 Infection 
 Tumor 
 Osteoporosis 
 Ankylosing spondylitis 
 Fracture 
 Deformity 

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 Inflammatory process 
 Cauda equina syndrome 
o 
Treated or untreated central nervous system impairment. 
o 
Meeting the criteria for surgery, including: 
 progressive motor deficit 
 sphincter impairment from neurological cause 
 disabling sciatic pain (in the absence of backache) lasting 6 weeks or more that is attributed to a 
compromised nerve root and demonstrated by magnetic resonance imaging or computed tomography 
o 
Oncologic disease during the previous 5 years. 
o 
Unexplained weight loss, fever, or chills. 
o 
Diagnosed upper urinary tract infection within last 28 days. 
o 
Patients identified during standard of care interview to have a history of intravenous drug use. 
o 
Immunocompromised host. 
o 
A severe comorbidity to include:  
 a detriment to the subjects overall well-being (e.g. painful disabling arthritic hip joints) 
 Cirrhosis 
 Ongoing dialysis  
o 
Radiating symptoms to lower extremities (sciatica). 
o 
History of bleeding disorders. 
o 
History of high blood pressure. 
o 
History of heart, kidney, liver or ulcer disease. 
o 
Allergic to analgesics or Non-steroidal anti-inflammatory agents (NSAIDs). 
o 
Pregnant or breastfeeding. 
o 
Initial pain rating of greater than 8/10 on initial intake evaluation 
o 
If the comprehensive metabolic panel is reviewed by the PI, and any of the values are outside a range deemed 
safe for the subject to be included in study. 
o 
If any of these four components of the complete blood count is reviewed by the PI, and any of the values are 
outside a range deemed safe for the subject to be included in study: 
 White blood cell count 
 Hemoglobin 
 Hematocrit 
 Platelets 
o 
Patients taking any of the following medications are excluded from participating, unless they agree to wash 
out for two weeks prior to entering the study: 
 Muscle relaxers of any type 
 Tramadol 
 Gabapentin 
 Pregabalin 
 Glucosamine 
 Narcotic pain medications 
 Non-steroidal anti-inflammatory agents (NSAIDs) 
* Patients taking naproxen must agree to wash out for two weeks prior to entering the study, but can begin 
taking it again, as prescribed, after Visit 1 where a baseline pain assessment is performed. 
 
7.  Number of Subjects:  TOTAL NUMBER OF SUBJECTS (nation-wide/study-wide):  NELLIS AFB 100 
 
8.  Use of an Investigational New Drug:  
a. 
Generic Name and IND Number: Methylsulfonylmethane (MSM), IND# 122180 
b. 
Sponsor holder of the IND Number: Paul Crawford, MD, LtCol, USAF, MC 
c. 
Justification for use: MSM plus standard of care naproxen improves symptoms of lower back pain. 
 
9.  Use of an Investigational Device: N/A 
 
10. Use of a Placebo:  Yes. The placebo is a capsule filled with rice flour. 
 
 

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PROTOCOL FOR CLINICAL INVESTIGATION – NON-EXEMPT HUMAN 
(Wilford Hall Ambulatory Surgical Center – WHASC) 
 
1.  Title: 
The use of Methylsulfonylmethane (MSM) in the treatment of low back pain. 
FWH20140075H                                                          
 
2.0.  Principal Investigator (PI): 
 
                           Nellis AFB PI: 
 
Name 
 
Paul Crawford 
Rank/Corps or Civilian Rating 
 
Col, USAF, MC 
Date of IRB Approved CITI Training & 
Date of Good Clinical Practice Training  
12/28/2017 
Branch of Service 
USAF 
AD Mil/DoD Civilian/Ctr/Non-DoD Civ 
AD 
Department  & Base 
 
Department of Medical Education, Nellis AFB 
Phone & Pager #  
(702) 653-3298 
E-Mail Address & AKO/DKO E-Mail Address 
Paul.F.Crawford.mil@mail.mil 
 
 
 
 
 
 
 
 
 
2.1.  Associate Investigators (AI):  See form A-2 Study Personnel 
 
2.2.  Research Assistants (RA) & Coordinators (RC):  See form A-2 Study Personnel 
 
2.3.  The research relevance of this protocol focuses on:  
[] Diagnosis 
[x] Treatment 
[] Medical Utilization/Managed Care 
[] Prevention 
[] Medical Readiness         [] Other 
 
2.4.  Location(s):   
a. Collaborating Facilities: None. 
b. Air Force Sites seeking Regional IRB: Mike O’Callaghan Military Medical Center/Nellis Air Force Base, Jill Clark 
c. 
List study sponsors: This study will be sponsored by Bergstrom Nutrition.  The collaborative research will be 
executed in accordance with 15 USC 3710a through a Cooperative Research and Development Agreement, between 
the 99th MDG and Bergstrom Nutrition.   The estimated fair market value of the support is $17,570.00. 
 
3.  Research Plan:  
 
3.1. Purpose:  
The purpose of this study is to assess whether Methylsulfonylmethane (MSM) plus standard of care naproxen improves 
symptoms of lower back pain versus standard of care naproxen plus placebo. 
 
3.2. Hypotheses, Research Questions or Objectives:  
Does the addition of MSM to standard of care treatment improve symptoms of lower back pain assessed by Roland-Morris 
Disability Questionnaire (RMDQ), pain level, and Pain Impact Questionnaire (PIQ-6)? 
   
3.3.  Significance:  
A lack of true clinical assessment of the usefulness of MSM in low back pain suggests that patients will continue to consume a 
product with a potential but unknown benefit. As a multidimensional approach to the treatment of low back pain is endorsed, 
the assessment of MSM on low back pain as an alternative or adjunctive therapy would be prudent. For this reason, we propose 
that a clinical trial be carried out to assess the impact of MSM on low back pain. 
 
3.4.  Military Relevance81:  
Low back pain is a common complaint of Tricare beneficiaries. In 2012, chronic pain treatment accounted for an approximate 
annual cost of $560-635 billion in direct medical treatment costs and lost productivity in the United States.  Despite these costs, 
the response of each individual to standard treatments varies greatly, often being under treated. Within the military, responses 
to traditional treatments and lost productivity are no different than the civilian communities but may have a far more reaching 
consequence as service men and women are often unable to perform their duties fully or deploy due to pain.  
 
While the DoD has developed tools for physicians to assess and treat low back pain, treatment is not always successful. As such, 
additional treatments options are needed which may yield positive results, without producing adverse side effects which may 
limit a member from duty or deployment. The proposed study of MSM will help define this new potential treatment, specifically 

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measuring improvement of pain and function. If found to be effective, this treatment may represent a significant step forward 
in providing excellent care to service members, while ensuring a force which is fit for duty. 
  
3.5.  Background and Review of Literature:  
Background:  Low back pain has been identified to account for 40% of all work related compensations filed in the US1. Overall, 
the lifetime prevalence of experiencing at least one episode of low back pain is believed to be 70-80%1. The etiology of low back 
pain is often considered multidimensional, and as such often requires a multidimensional approach to its treatment2,3.  Even 
when a multidimensional treatment plan is created or proposed for patients, many endorse the concurrent use of 
complementary and alternative medicines, either as adjunctive therapy or in place of offered treatment. This is especially true 
when patients have concerns about the cost or delayed receipt of conventional care4. While the true percent of patients who 
endorse the use of complementary or alternative medicines is unknown, reports suggest that 9% to 65% of the population has or 
currently uses treatments other than those prescribed by their physician5.  Back pain has been noted to be the principle reason 
for using CAM4,6 Top cited uses of CAM include prayer5, nonvitamin, nonmineral, natural products, deep breathing exercises, 
meditation, chiropractic, or osteopathic manipulation, massage, and yoga7.  
 
Sources used by patients for acquiring information on various CAM therapies vary from internet, to personal testimonial, to 
books published by a variety of health professionals.  Among the many published books, H procumbens, S alba, topical capsasin 
compresses, and methylsulfonylmethane (MSM) are often cited as a supplemental agent which can be used for a variety of 
orthopedic ailments ranging from arthritis to low back pain8,9.  Specifically, MSM accounts for 4.1% of nonvitamin, nonmineral  
products used4. While several clinical trials and systematic reviews have been aimed at testing H procumbens, S alba, topical 
capsasin compresses for low back pain, clinical trials assessing the role MSM may play in the treatment of low back pain are 
largely lacking. Despite this, it remains widely cited as an agent which may be used in the treatment of low back pain8,10 as well 
as many other illnesses11.    
 
Research of Interest: One area in which MSM has undergone some degree of investigation is its use as an adjunct therapy for 
osteoarthritis12-19.  In each study of patients with OA, MSM was associated with decreased patient pain and increased function. 
Variation in method used to measure effectiveness was noted from study to study, the most frequent assessments used 
including Oswestry Disability Questionnaire,  Roland-Morris Disability Questionnaire, Visual Analogue Scale (for pain intensity), 
and Western Ontario and McMaster University Osteoarthritis Index visual analogue scale (WOMAC).  As pointed out by  We et 
al, the variability of effect found in the use of MSM in osteoarthritis  approaches 0% with studies noting a significant 
improvement in most measured symptoms. This suggests that the effect of MSM has on pain caused by osteoarthritis 
consistently improves symptoms from study to study. Because each study contained various shortcomings in terms of study 
design (small treatment groups, possible un-blinding, questionable open-label trials, possible co-interventions, unstated 
compliance the use of MSM in the treatment of osteoarthritis), MSM has not been recommended for treatment of OA in all 
patients. However, data currently are supportive of its use.  
 
Pharmacology of MSM: Methysulfonylmethane [(CH3)2SO2] is a largely tasteless, odorless, white, crystalline solid which is water 
soluble20. It occurs naturally in the environment and is synthesized in the human body18 as a byproduct of dietary DMSO21 where 
15% of consumed DMSO is converted into MSM 11.  MSM is believed to have anti-inflammatory properties as demonstrated by in-
vitro studies which suggest MSM may blunt inflammatory processes22.  However, studies have demonstrated that MSM does 
not interact with the COX or PG synthesis pathways23 or by decreasing ESR or CRP levels13. While DMSO and MSM are believed to 
block conduction of peripheral C-fibers15, slow the proliferation of smooth muscle and endothelial cells, and decrease the 
binding, uptake, and degradation of LDL by fibroblasts27,28, decrease urine MDA levels in humans, and delay chemically-induced 
colon cancer onset in rats13, no clear anti-inflammatory mechanism of action has been elicited. 
 
While MSM has not received FDA approval for any specific ailment, DMSO, the parent compound of MSM (see above) has been 
FDA approved for the treatment of intersitital cystitis when infused as a 50% solution71. MSM continues to be used (CAM) for 
illnesses including  OA, back pain, fibromyalgia, tendinitis, carpal-tunnel syndrome, dental pain, asthma, food allergies, asthma, 
rheumatoid arthritis, SLE, scleroderma, hypertension, and elevated serum cholesterol among others20,24.  
 
Safety: MSM is rated as “Probably Safe” by the Natural Medicines Comprehensive Database when given in 2.6 to 6 grams/day, 
up to 12 weeks24. Studies in rats given 1.5-2.0 g/kg/day orally showed no mortality, adverse effects or clinical signs of toxicity, 
effects on body weight gain, or gross lesions68.  In a study by Kim et al15 on MSM and osteoarthritis, no change or adverse event 
was noted in liver or renal function, hematology studies (CBC), stool assessment for occult bleeding or lipid profile, or urinalysis.  
In a similar study, Vidyasagar et al78 found similar results with no CBC, Serum Glucose, Urea, Creatinine or AST/ALT. Taking all of 
this into consideration, the FDA previously labeled MSM as Generally Recognized as Safe in 200879. The LD50 is currently 
unknown due to the fact that maximum dose given to date (20g/kg/day) failed to produce death in animal studies69. MSM 
should be avoided during pregnancy and lactation due to insufficient reliable information available (no studies have specifically 

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looked at its use during pregnancy). Prior to the recommendation to limiting the daily dose to 6 grams/day in humans, some 
physicians recommended up to 20 g/day, which approximates to 300 mg per kg/day70. 
 
Adverse Reactions13,24: When dosed orally, nausea, diarrhea, bloating, headache, fatigue, insomnia, and difficulty concentrating 
have been reported. These adverse reactions however, do not appear to occur any more frequently in groups exposed to MSM 
than placebo in clinical trials13. There is no known drug-food, drug-drug, or drug-lab test interactions known24. 
 
Proposed use of MSM in Low Back Pain: As noted previously, MSM accounts for 4.1% of all nonvitamin, nonmineral CAM 
therapies used and is often cited as a remedy for back pain.  Tant et al note that in a trial of glucosamine containing MSM, both 
yield symptomatic relief in patients with low back pain, individually and when taken together25.  Interestingly, trials such as that 
performed by Usha et al included MSM in the formulation of Glucosamine when assessing its impact on osteoarthritis14.  
However, additional information on the impact MSM may have on low back pain is lacking. Furthermore, of the 462 trials for low 
back pain registered with clinicaltrials.gov, none is designed to assess the impact of MSM on low back pain26.  
 
Patients continue to access information on CAM through a variety of sources. A lack of true clinical assessment of the usefulness 
of MSM in low back pain suggests that patients will continue to consume a product with a potential but unknown benefit. As a 
multidimensional approach to the treatment of low back pain is endorsed, the assessment of MSM on low back pain as an 
alternative or adjunctive therapy would be prudent. For this reason, we propose that a clinical trial be carried out to assess the 
impact of MSM on low back pain. 
 
Selection of Outcome Measurements in Low Back Pain: Clinical outcome measurements for low back pain have been studied by 
many groups. Reviews of various outcome measurements for low back pain have identified up to 36 distinct outcome 
measurements36. However, only a select number of them are considered valid or reliable. Studies may be unidimensional, 
focusing only on pain, or multidimensional where focus is placed not only on pain but on the extent to which the severity of pain 
impacts activity or emotional function30,35. No Gold Standard exists for evaluating disability in low back pain34 though authors 
suggest that prospective32, patient/self-reported31,33,35 measures of pain are ideal.  Some authors suggest that surrogate markers 
such as analgesic use should not be used when assessing a patient’s clinical status32. However, because the etiology of low back 
pain is often multifactorial, multiple measurements of low back pain are often recommended when measuring the impact any 
given intervention has on low back pain29.  
 
Three general areas of assessment common to low back pain include pain, function, and quality of life29. Of these areas, 
assessment of pain itself is often the focus of studies due to the belief that a prerequisite to the management of pain is the 
accurate assessment of the same47. This focus is further supported by the finding that the correlation between self-reported 
pain and self-reported function and objective measures of function are significant but weak48,49,50. The other areas are assessed 
as they give insight into the overall impact the treatment has on the patient (clinical significance). Studies commonly used to 
assess these areas include: 
 
-Pain: Visual Assessment Scale (VAS)29, 31, 37, Verbal Rating Scales (VRS)32, and Numerical Rating Scale (NRS)32,38 
 
-Function: Oswestry Low Back Pain Disability Questionnaire/Index (ODI) 29,37, Roland-Morris Disability Questionnaire 
(RMDQ)29,37, Quebec Back Pain Disability Scale34,37 
 
-Quality of Life: SF-36, 12, or PIQ-629,35,37,67, Patients Global Assessment of Response to Therapy (PGART)31 
 
Pain: We recommend the VAS. The VAS appears in most studies of low back pain and has specifically been recommended29. 
Mannion et al also suggest that most patients treat the VRS and NRS as a VAS by simplifying each respective numerical scale to 
approximate that seen in the VAS. When the scale is properly explained, it has been shown to be reproducible and easy to 
interpret35. However, this choice may be considered arbitrary as studies measuring the variance between various numerical 
scales suggest any numerical scale may be used with expected reproducible results35. One advantage of using the NRS is that 
the Minimally Clinically Important Difference (MCID) has already been calculated as 235,38. With respect to expected outcomes, 
Farrar suggests that a relative treatment difference in pain level of 33-50% on any scale is considered clinically meaningful40. 
 
Function: We recommend the Roland-Morris Disability Questionnaire. While both the ODI and RMDQ are reliable, valid, and 
require only 5 minutes to complete, the RMDQ is the most studied of all functional outcome assessments35. Published Mean 
Detectable Change (MDC) is available for both of these studies though it varies from study to study, based on the initial 
measured level of function. Generally, a low initial score indicates that less than a 5 point difference is needed to identify a 
detectable change. Higher baseline scores may necessitate as much as a 8-9 point difference to identify a change. Roughly, a 5 
point difference correlates to a 20% change on the scale35. Other authors such as Bombardier et al suggest that a 2-3 point 
difference is a MCID41. 
 

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Quality of Life:  We propose the use of the PIQ-6/R. While the SF-36 and SF-12 has been well studied and approved by the 
Medical Outcome Trust51, shorter questionnaires which measure the impact of pain on the quality of life have been developed 
and include the SF-6D and PIQ-6/PIQ-R35,51,67 which may provide reliable information.  While the SF-36 has been more widely 
published35, the SF-12 and PIQ-6/R are routinely used. Limited data has been published on the MDC or MCID for the SF-36 but has 
been described by Walters et al65. The PIQ-6 is ideal for the current study due to its high internal validity and correlation with 
pain visual analog and numerical rating scales67. An additional reason for using the PIQ-6 rather than the SF-6 includes concerns 
that the SF-6 may overestimate baseline values and underestimate change66.  Sheldon et al31 suggest that the correlation 
between RMDQ and VAS ranged from 0.657 and  0.703, and the VAS and PGART from 0.677 and 0.738, suggesting that results 
are similar enough that assessments may be simplified (eliminate one of these studies). Because the PIQ-6 also highly correlates 
with VAS, it was selected in place of the PGART. Similar correlation results have been reported by Kovacs et al at days 15 and 60 
of follow up, but not on initial (day 1)52 making long term follow up important. The PIQ-6/R satisfies this time course as it is 
designed for a 4 week follow up. Reasons for including a measure of quality of life (vs pain only) is that measuring the quality of 
life helps determine the clinical significance of statistical findings39. 
 
Patient Selection: It has been noted that the natural course of acute low back pain is such that rapid improvement of pain, 
disability, and return to work is experienced in the majority of patients by 4 weeks56. Further improvement is then noted up to 3 
months55,56. Of the patients who go on to develop chronic low back pain, 90% endorse stable pain and disability55. Kovacs et al 
note that the extent to which disability can be attributed to pain itself (vs psychosocial and cognitive measures) is highest in the 
acute setting (pain <14 days)53. Disability from chronic low back pain (pain >12 weeks in duration33) is also influenced by multiple 
factors to include both pain itself and psychosocial facotrs42.  Despite this finding, attempts to address the psychosocial aspects 
with antidepressants have inconsistently shown true benefit58,60.   Even though chronic low back pain is a multidimensional 
problem, authors such as Kovacs et al agree that the enduring presence of pain can predict disability, and disability in turn may 
predict quality of life. Treatment plans for patients with chronic low back pain encompass a variety of treatments from 
advice/continued activity to pain medications to use of complementary and alternative medicine43-46,49,54. Yet despite this 
multifaceted approach, a substantial number patients continue to experience pain and disability, albeit at a stable level55,56. 
Because of this stability, patients with chronic low back pain would be ideal study population to assess the impact of MSM on 
low back pain.  
 
MSM has not been well studied in low back pain. Tant et al report that it may be helpful in the treatment of chronic low back 
pain57 when coupled with glucosamine complex. However, their study used a small number of patients and did not include a 
true placebo control for glucosamine/MSM. Further information on MSM and chronic low back pain is otherwise lacking.  
 
Adverse Side Effects:  As noted above, Kim et al13. reported adverse side effects of bloating, constipation, indigestion, fatigue, 
decreased concentration, insomnia and headache, though these symptoms were not any more prevalent in the group taking 
MSM than the placebo group.  
 
Proposal of Materials and Methods:  Selection of proper follow up time has been based on studies of MSM in osteoarthritis. 
Follow up time ranges from 213 to 12 weeks12. In the study by Kim et al13, efficacy was not noted until 4 weeks into the study. This 
improvement was even more notable at 8 and 12 weeks than at 4 suggesting that improvement in symptoms may require longer 
exposure MSM. For this reason, the impact MSM on low back pain, function and quality of life should be carried out to at least 12 
weeks.  
 
The use of 4 week intervals for reassessment mirrors the protocol by Kim et al. This is convenient considering the PIQ-6/R was 
designed for a 1(acute) or 4 week (chronic) follow up. 
 
Inclusion and Exclusion Criteria for this study will be similar to the common criteria from various studies on Low Back Pain42-
44,52,55, 58, 61.  
Studies of MSM and osteoarthritis have recommended MSM dosing ranging from 500mg TID to 3 g BID12,13. Doses of 6 g daily 
are considered safe13,24. As noted above, studies in rats found that doses 5-7 times the maximum recommended daily amount 
may be given without any appreciable toxicity15,68. Human studies using >6gm/day have not been performed. MSM will be given 
in the dose of 1500mg x2 Tabs, BID. Standard of care naproxen is typically defined as a dose of 225-550 mgs twice a day although 
it may vary depending on the provider. 
 
3.5.1. Bibliography:  
1. Handrakis JP, Friel K, Hoeffner F, Akinkunle O, Genova V, Isakov E, Mathew J, Vitulli F, Key Characteristics of Low Back Pain 
and Disability in College-Aged Adults: a Pilot Study, Archives of Physical Medicine and Rehabilitation. 2012 – Manuscript 
accepted for publication.  

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2. Maiers MJ, Westrom KK, Legendre CG, Bronfort G. Intergrative care for the management of Chronic Pain: use of a clinical 
care pathway. Prim Care Clin Office Pract. 2010. 37; 407-421. 
3. Teets RY, Dahmer S, Scott E. Integrative Medicine Approach to Chronic Pain. 
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6. Barnes PM, Powell-Briner E, McFann K, Nahin RL. Complementary and Alternative Medicine Use Among Adults: United 
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Healing. 2009. 5(2)  71-73. 
8. Perscription for Nutritional Healing: A Practical Guide from A-to-Z Reference to Drug-Free Remedies Using Vitamins, 
Minerals, Herbs & Food Supplements. 5th Edition. Phyllis A. Balch, CNC.  October 2010. 
9. Gagneir JJ, Maurits WVT, Berman B, Bombardier C. Herbal Medicine for Low Back Pain, A Cochrane Review. Spine 
2007;32:82–92 
10. http://www.natural-remedies-review.com/msm.html  
11. Life&Health Library, NBC. Accessed 8/March/2012.URL: http://findarticles.com/p/articles/mi_m0FDN/is_4_8/ai_111303985/.  
12. Debbi EM, Agar G, Fichman G, Bar Y, Kardosh R, Halperin N, Elbaz A, Beer Y, Debi R. Efficacy of methylsulfonylmethane on 
osteoarthritis of the knee: a randomized controlled trial. BMC Complementary and Alternative Medicine 2011, 11:50 
13. Kim LS, Axelrod LJ, Howard P, et al. Efficacy of MSM in osteoarthritis pain of knee: a pilot clinical trial. Osteroarthritis and 
Cartilage. 2006. 14(3) 286-294 
14. Usha PR, Naidu MUR. Randomised, Double-Blind, Parallel, Placebo-Controlled Study of Oral Glucosamine, 
Methylsoulfonylmethane and their Combination in Osteoarthritis. Clinical Drug Investigation. 2004;24:353-63 
15. Brien S, Prescott P, Bashir N, Lewith H, Lewith G. Systematic review of the nutritional supplements dimethyl sulfoxide 
(DMSO) and methylsulfonylmethane (MSM) in the treatment of osteoarthritis", Osteoarthritis and Cartilage. 2008;16:1277 
16. LeBlanc KE, LeBlanc LL. Musculoskeletal Disorders. Prim Care Clin Office Pract 37 (2010) 389-406 
17. Debi R, Fichman Y, Bar Ziv R, The role of MSM in knee osteoarthritis: a double-blind, randomized, prospective study. 
Osteoarthritis Cartilage 2007;15(3 supplement):C231 
18. Debbi EM, Agar G, Fichman G, Bar Y, Kardosh R, Halperin N, Elbaz A, Beer Y, Debi R. Efficacy of methylsulfonylmethane 
supplementation on osteoarthritis of the knee: a randomized controll study. BMC Complementary and Alternative 
Medicine 2011, 11:50 
19. We SR, Jeong E, Koog YH, Min B. Effect of nutraceuticals on knee osteoarthritis: Systematic Review.   African Journal of 
Biotechnology 2012. 11(12), 2814-2821 
20. Cronin JR, Ballen K. The biochemistry of alternative therapies: methylsulfonylmethane: nutraceutical of the next century? J 
Altern Complement Med 1999;5(6):386-389 
21. Pearson TW, Dawson HJ, Lackey HB. Natural occurring levels of dimethyl sulfoxide in selected fruits, vegetables, grains, 
and beverages. J Agric Food Chem 1981;29:1089-1091 
22. Beilke MA, Collins-Lech C, Sohnle PG. Effects of dimethyl sulfoxide on the oxidative function of human neutrophils. J Lab 
Clin Med 1987;110:91-96) 
23. Ebisuzaki K. Aspirin and methylsulfonyl-methane (MSM): a search for common mechanisms, with implications for cancer 
prevention. Anticancer Res 2003;23:453-458 
24. Natural Medicines Comprehensive Database.  Accessible at 
https://naturaldatabase.therapeuticresearch.com/logon.aspx?s=ND&cs=dod   
25. Tant L, Gillard B, Appleboom T. Open-label, randomized, controlled pilot study of the effects of a glucosamine complex on 
Low Back Pain. Current Therapeutic Research. 2005. 66(6) 511-521. 
26. Clinicaltrial.gov URL http://clinicaltrials.gov/ct2/results?cond=%22Low+Back+Pain%22. Accessed 8/March/2012. 
27. Alam SS, Layman DL. Dimethyl sulfoxide as a cholesterol-lowering agent in cultured fibroblasts exposed to low density 
lipoproteins in culture. Biochim Biophys Acta 1982;710:306-313 
28. Layman DL. Growth inhibitory effects of dimethyl sulfoxide and dimethyl sulfone on vascular smooth muscle and 
endothelial cells in vitro. In Vitro Cell Dev Biol 1987;23:422-428 
29. Chapman JR, Norvell DC, Hermsmeyer JT, Bransford RJ, DeVine J, McGirt MJ, Lee MJ. Evaluating common outcomes for 
measuring treatment success for chronic low back pain. Spine 2011. 1;36(21 Suppl):S54-68. 
30. Vellucci R.  Heterogeneity of chronic pain.  Clin Drug Investig. 2012 Feb 22;32 Suppl 1:3-10. 
31. Sheldon EA, Bird SR, Smugar SS, Tershakovec  AM. Correlation of measures of pain, function, and overall response: results 
pooled from two identical studies of etoricoxib in chronic low back pain. Spine 2008. Mar 1;33(5):533-8. 
32. Mannion AF, Balagué F, Pellisé F, Cedraschi C. Pain measurement in patients with low back pain Nat Clin Pract Rheumatol. 
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33. Malliou P, Gioftsidou A, Beneka A, Godolias G. Measurements and evaluations in low back pain patients. Scand J Med Sci 
Sports. 2006 Aug;16(4):219-30.  
34. Calmels P, Béthoux F, Condemine A, Fayolle-Minon I. Low back pain disability assessment tools. Ann Readapt Med Phys. 
2005 Jul;48(6):288-97. Epub 2005 Apr 26. [Article in French] 
35. Resnik L, Dobrykowski E. Outcomes measurement for patients with low back pain. Orthop Nurs. 2005 Jan-Feb;24(1):14-24. 
36. Grotle M, Brox JI, Vøllestad NK. Functional status and disability questionnaires: what do they assess? A systematic review 
of back-specific outcome questionnaires.  Spine 2005. 30(1):130-40. 
37. Müller U, Duetz MS, Roeder C, Greenough CG.  Condition-specific outcome measures for low back pain. Part I: validation. 
Eur Spine J  2004. 13(4):301-13. Epub 2004 Mar 17. 
38. Childs JD, Piva SR, Fritz JM. Responsiveness of the numeric pain rating scale in patients with low back pain. Spine 2005. 
30(11):1331-4. 
39. Spilker B. Guide to clinical trials. New York: Raven Pr; 1991. p507 
40. Farrar JT. Deﬁning the clinically important difference in pain outcome measures. Pain 2000;88:287-4 
41. Bombardier C, Hayden J, Beaton DE. Minimal clinically important difference. Low back pain: outcome measures. J 
Rheumatol 2001;28:431-8. 
42. Melloh M, Elfering A, Egli Presland C, Röder C, Hendrick P, Darlow B, Theis JC. Predicting the transition from acute to 
persistent low back pain. Occup Med (Lond). 2011 Mar;61(2):127-31. Epub  
43. Nadler SF, Steiner DJ, Erasala GN, Hengehold DA, Abeln SB, Weingand KW. Continuous Low-Level Heatwrap Therapy for 
Treating Acute Non-Specific Low Back Pain. Arch Phys Med Rehabil 2003. 84; 329-334 
44. Nadler SF, Steiner DJ, Erasala GN, Hengehold DA, Abeln SB, Weingand KW. Continuous Low-Level Heat Wrap Therapy 
Provides More Efﬁcacy Than Ibuprofen and Acetaminophen for Acute Low Back Pain. Spine 2002. 27(10); 1012–1017. 
45. Roelofs PDDM, Deyo RA, Koes BW, Scholten RJPM, van Tulder MW. Nonsteroidal Anti-inflammatory drugs for low back 
pain: An Updated Cochrane Review. Spine 2008. 33(16); 1766-1774 
46. Pohjolainen T, Jekunen A, Autio L, Vuorela H. Treatment of Acute Low Back Pain With theCOX-2–Selective Anti-
Inﬂammatory Drug Nimesulide Results of a Randomized, Double-Blind Comparative Trial Versus Ibuprofen. Spine 2000. 
25(12); 1579-1585. 
47. Charette SL and Ferrell BA. Rheumatic diseases in the elderly: assessing chronic pain. Rheum Dis Clin North Am 2007. 33: 
109-122. 
48. Ferrer M et al. Validation of minimum outcome core set in the evaluation of patient with back pain. Spine (2006). 31:1372-
1379; discussion 1380 
49. Mannion AF et al. Active therapy for chronic low back pain. Part 3. Factors influencing self-rated disability and its change 
following therapy. Spine 2001. 26: 920-929. 
50. Gronblad M et al. Relationships between spinal mobility, physical performance tests,  pain intensity and disability 
assessments in chronic low back pain patients. Scand J Rehabil Med 1997. 29: 17-24. 
51. Medical Outcomes Trust. URL: http://www.outcomes-trust.org/instruments.htm.  Accessed 16 March 2012. 
52. Kovacs FM, Abraira V, Zamora J, Fernández C.  The transition from acute to subacute and chronic low back pain: a study 
based on determinants of quality of life and prediction of chronic disability. Spine 2005. 30(15):1786-92. 
53. Kovacs FM, Abraira V, Zamora J, et al. Correlation between pain, disability and quality of life in patients with common low 
back pain. Spine 2004;29: 206–10. 
54. Liddle SD, Gracey JH, Baxter GD. Advice for the management of low back pain: A systematic review of randomised 
controlled trials. Manual Therapy 2007. 12; 310–327 
55. Verkerk K, Luijsterburg PA, Ronchetti I, Miedema HS, Pool-Goudzwaard A, van Wingerden JP, Koes BW. Course and 
prognosis of recovery for chronic non-specific low back pain: design,  therapy program and baseline data of a prospective 
cohort study. BMC Musculoskelet Disord. 2011 Nov 2;12:252 
56. Pengel LH, Herbert RD, Maher CG, Refshauge KM: Acute low back pain: systematic review of its prognosis. BMJ 2003, 
327:323 
57. Tant L, Gillard B, Appleboom T. Open-label, randomized, controlled pilot study of the effects of a glucosamine complex on 
Low Back Pain. Current Therapeutic Research. 2005. 66(6) 511-521. 
58. White AP, Arnold PM, Norvell DC, Ecker E, Fehlings MG. Pharmacologic management of low back pain: synthesis of the 
evidence. Spine 2011. 1;36(21 Suppl):S131-43 
59. Medscape PDA Resource: Naproxen-Adult Doses & Uses-Pain. Accessed 28 March  2012. 
60. 
Chou R, Huffman LH; American Pain Society; American College of Physicians.  Medications for acute and chronic low 
back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. 
Ann Intern Med 2007. 2;147(7):505-14. 
61. Bigos S, Bowyer O, Braen G, et al. Acute Low Back Problems in Adults. Clinical Practice Guideline, Quick Reference Guide 
Number 14. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care 
Policy and Research, AHCPR Pub. No. 95–0643, December 1994 
62. http://www.worldimagenaturals.com/products/msm/ 

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63. http://www.drugstore.com/natures-way-msm-1000mg-pure-optimsm-tablets/qxp143095 
64. http://www.gnc.com/product/index.jsp?productId=2133431 
65. Walters SJ and Brazier JE. What is the relationship between the minimally important difference and health state utility 
value? The case of the SF-6D. Health and Quality of Life Outcomes 2003, 1:4  
66. 
Harrision MJ, Lunt M, Verstappen SMM, Watson KD, Bansback NJ, Symmons DPM. Exploring the validity of estimating 
EQ-5D and SF-6D utility values from the health assessment questionnaire in patients with inflammatory arthritis. Health 
and Quality of Life Outcomes 2010, 8:21 
67. Becker J, Schwartz C, Saris-Baglama RN, et al. Using Item Response Theory (IRT) for developing and evaluating the Pain 
Impact Questionnaire (PIQ-6TM). Pain Med 2007;8(S3):S129-S144 
68. 
 Horváth K, Noker PE, Somfai-Relle S, et al. Toxicity of methylsulfonylmethane in rats. Food Chem Toxicol 2002;40:1459-
62 
69. 
Hixson O.  Acute intragastric toxicity (LD-50). Dimethyl sulfone (methylsulfonylmethane, MSM). Laboratory of Vitamin 
Technology, Inc., Chicago, Illinois, August 21, 1958. 
70. Jacob S, Lawrence RM, Zucker M. The Miracle of MSM: The Natural Solution for Pain. New York: Penguin-Putnam, 1999 
71. Melchior D, Packer CS, Johnson TC, Kaefer M. Dimethyl Sulfoxide: Does It Change the Functional Properties of the Bladder 
Wall? Journal of Urology. 170(1):253-258, July 2003. 
72. Ludington E, Dexter F.  Statistical Analysis of Total Labor Pain Using the Visual Analog Scale and Application to Studies of 
Analgesic Effectiveness During Childbirth.  Anesth Analg.  1999; 87: 723-727. 
73. Myles PS, Troedel S, Boquest M, Reeves M.  The Pain Visual Analog Scale: Is It Linear or Nonlinear? Anesth Analg. 1999; 89: 
1517–1520. 
74. . Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: A flexible statistical power analysis program for the social, 
behavioral, and biomedical sciences. Behavior Research Methods. 2007; 39 (2): 175-191. 
75. R Development Core Team (2011). R: A language and environment for statistical computing. R Foundation for Statistical 
Computing,   Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org/. 
76. Vidyasagar S, Mukhyaprana P, Shashikiran U, Sachidananda A, Rao S, Bairy KL, Aidga S, Jayaprakash B. Effecacy and 
Tolerability of Glucosamine Chondroitin Sulfate- Methyl Sulfonyl Methane (MSM) in Osteoarthritis of Indian Patients. 
Iranian Journal of Pharmacology & Therapeutics. 2004, 3:61-65. 
77. Tarantino, LM. Agency Response Letter GRAS Notice No. GRN 000229, CFSAN/Office of Food Additive Safety. 2008. 
http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm153891.htm 
78. Kotton CN and Freedman DO. CDC Publication: Immunocompromised Travelers, Chapter 8. 
http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-8-advising-travelers-with-specific-needs/immunocompromised-
travelers 
79. Office of the Secretary of Defense: Report to the Congress, The Implementation of a Comprehensive Policy on Pain 
Management by the Military Health Care System. September 2012 
   
3.6.  Research Design and Methods:  
We will recruit male and female NELLIS AFB DoD beneficiaries between the ages of 18-65 years old with symptoms of lower back 
pain from any of the clinics at Nellis Air Force Base.  Patients taking Muscle relaxers of any type, Non-steroidal anti-inflammatory 
agents (NSAIDs), Tramadol, Gabapentin, Pregabalin, agree to wash out for two weeks prior to entering the study. 
Randomization will be performed by the research coordinator. Both Investigators and subjects will be blinded to study 
assignments. 
 
Screening Visit: 
• 
Obtain signed Informed Consent Document and HIPAA Authorization. 
• 
Review inclusion/exclusion criteria. 
• 
Record: name, race ethnicity, race, date of birth, age, sex, height (in inches), weight (in pounds), blood pressure, email 
address, phone number, history of lower back surgeries, medical history, concomitant medications, and record the 
amount of naproxen prescribed as standard of care.  
• 
Subjects will have the following research-driven blood test drawn via 1 venipuncture (5-10 mls, approximately 1-2 
teaspoons of blood drawn for each test) which include: 
o Women of childbearing potential will have a serum pregnancy test. 
o  Comprehensive metabolic panel (liver function, renal function, plasma glucose tests). 
*Subjects who have had a comprehensive metabolic panel test within the one week prior to this visit will not need to 
have this test repeated unless they are abnormal. 
o Complete Blood Count. 
*Subjects who have had a complete blood count test within the one week prior to this visit will not need to have this test 
repeated unless they are abnormal. 
 

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Visit 1/Day 1 (within 1 week of Screening Visit): 
• 
Subjects will be randomized by the research coordinator.  Both subjects and investigators will be blinded to the study 
group assignments: 
o Group 1 will take by mouth three 1000 mg capsules twice a day (6000 mgs) of MSM plus standard of care naproxen. 
o Group 2 will take by mouth three placebo capsules twice a day plus standard of care naproxen.  
• 
Subjects will be asked to complete the following questionnaires: 
o RMDQ 
o PIQ-6 
• 
Subjects will be asked “On a scale of 0-10, with 10 being the worst pain, what is your current level of pain”. 
• 
Subjects will be asked if they are undergoing any other treatment for back pain, when the last treatment was, and 
whether or not they were satisfied.  
• 
Subjects will be given a 12 week supply of the study pills and reminded to take the pills as instructed. 
• 
Subjects will be given a Study Diary and will be instructed to record any missed dose of their study pills, record how much 
standard of care naproxen taken, and to bring the Study Diary to next visit. 
 
Visit 2/Week 4: 
• 
Record: Weight (in pounds), blood pressure, history of lower back surgeries, medical history, and concomitant 
medications. 
• 
Subjects will be asked to complete the following questionnaires: 
o RMDQ 
o PIQ-6 
• 
Subjects will be asked “On a scale of 0-10, with 10 being the worst pain, what is your current level of pain”. 
• 
Research staff will record whether subject had any side effects to report. 
• 
Subjects will have their study medications refilled. 
• 
Research staff will collect the subject’s Study Diary, issue them a new one, and remind them to bring it with them to the 
next study visit. 
• 
Research staff will remind subjects to take the pills as instructed. 
• 
Subjects will have the following research-driven blood test drawn via 1 venipuncture (5-10 mls, approximately 1-2 
teaspoons of blood drawn for each test) which include: 
o Comprehensive metabolic panel (liver function, renal function, plasma glucose tests). 
*Subjects who have had a comprehensive metabolic panel test within the one week prior to this visit will not need to 
have this test repeated unless they are abnormal. 
o Complete Blood Count. 
*Subjects who have had a complete blood count test within the one week prior to this visit will not need to have this test 
repeated unless they are abnormal. 
 
Visit 3/Week 8: 
• 
Record: Weight (in pounds), blood pressure, history of lower back surgeries, medical history, and concomitant 
medications. 
• 
Subjects will be asked to complete the following questionnaires: 
o RMDQ 
o PIQ-6 
• 
Subjects will be asked “On a scale of 0-10, with 10 being the worst pain, what is your current level of pain”. 
• 
Research staff will record whether subject had any side effects to report. 
• 
Subjects will have their study medications refilled. 
• 
Research staff will collect the subject’s Study Diary, issue them a new one, and remind them to bring it with them to the 
next study visit. 
• 
Research staff will remind subjects to take the pills as instructed and to return the bottle to the research staff at the 
next visit. 
• 
Subjects will have the following research-driven blood test drawn via 1 venipuncture (5-10 mls, approximately 1-2 
teaspoons of blood drawn for each test) which include: 
o Comprehensive metabolic panel (liver function, renal function, plasma glucose tests). 
*Subjects who have had a comprehensive metabolic panel test within the one week prior to this visit will not need to 
have this test repeated unless they are abnormal. 
o Complete Blood Count. 
*Subjects who have had a complete blood count test within the one week prior to this visit will not need to have this test 
repeated unless they are abnormal. 
 

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Visit 4/Week 12 *SUBJECTS STOP TAKING STUDY PILLS AT THIS VISIT: 
• 
Record: Weight (in pounds), blood pressure, history of lower back surgeries, medical history, and concomitant 
medications. 
• 
Subjects will be asked to complete the following questionnaires: 
o RMDQ 
o PIQ-6 
• 
Subjects will be asked “On a scale of 0-10, with 10 being the worst pain, what is your current level of pain”. 
• 
Research staff will record whether subject had any side effects to report. 
• 
Research staff will collect the subject’s Study Diary. 
• 
Research staff will collect the study pills. 
• 
Subjects will have the following research-driven blood test drawn via 1 venipuncture (5-10 mls, approximately 1-2 
teaspoons of blood drawn for each test) which include: 
o Comprehensive metabolic panel (liver function, renal function, plasma glucose tests). 
*Subjects who have had a comprehensive metabolic panel test within the one week prior to this visit will not need to 
have this test repeated unless they are abnormal. 
o Complete Blood Count. 
*Subjects who have had a complete blood count test within the one week prior to this visit will not need to have this test 
repeated unless they are abnormal. 
 
Final Visit 5/Week 16: 
• 
Record: Weight (in pounds), blood pressure, history of lower back surgeries, medical history, and concomitant 
medications. 
• 
Subjects will be asked to complete the following questionnaires: 
o RMDQ 
o PIQ-6 
• 
Subjects will be asked “On a scale of 0-10, with 10 being the worst pain, what is your current level of pain”. 
• 
Subjects will be asked if they are undergoing any other treatment for back pain, when the last treatment was, and 
whether or not they were satisfied.  
• 
Subject will be asked if they have taken any medications for pain since their last visit. 
• 
Research staff will record whether subject had any side effects to report. 
• 
Subjects will have the following research-driven blood test drawn via 1 venipuncture (5-10 mls, approximately 1-2 
teaspoons of blood drawn for each test) which include: 
o Comprehensive metabolic panel (liver function, renal function, plasma glucose tests). 
*Subjects who have had a comprehensive metabolic panel test within the one week prior to this visit will not need to 
have this test repeated unless they are abnormal. 
o Complete Blood Count. 
*Subjects who have had a complete blood count test within the one week prior to this visit will not need to have this test 
repeated unless they are abnormal. 
 
DIRECTIONS FOR TAKING MEASUREMENTS: 
Directions for weighing subjects:  Have subject remove his/her shoes and empty pockets of any items prior to stepping on the 
scale.  Weight should be recorded to the nearest ½ pound (for example 150.5#). 
 
Directions for taking height:  Have subjects remove their shoes before taking their height.  Height should be recorded to the 
nearest 1/2 inch (for example 60.5”). 
 
Directions for taking blood pressure: Have subjects sit for 5 minutes before taking blood pressure. 
 
VISIT WINDOWS: Visits will have a 1 week visit window. If a subject fails to come in within this visit window, they will be instructed to 
bring in any unused study pills and removed from the study. 
 
ADHERENCE TO STUDY ASSIGNMENTS: Adherence to study medication will be assessed via review of the “Study Medication 
Diary”. Compliance will be recorded both in paper format and in the electronic data collection tool. If a subject misplaces their 
Study Medication Diary, they will be asked to reproduce it from memory to the best of their ability. Subjects will be instructed to 
bring back all of the bottles regardless of whether there are empty or contain missed doses. 
 
If a subject misses a dose, regardless of the amount, they will be encouraged to document this in their study diary and resume 
taking their pills. All subjects will remain in the study and continue with all the study related visits. 

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Non-Exempt Human Research Study 
 
If a subject misplaces or loses their study medication, they will be instructed to return to the research department and will be 
given a new bottle of their assigned study medication.  Since the research coordinator is not blinded, they will be able to give 
the medication that the subject was assigned. 
 
If a subject forgets to bring their study medication in for their visit, they will be instructed to bring it in at their earliest 
convenience. 
 
WITHDRAWAL PROCEDURES: If at any time during the study, the subject decides to withdraw consent or if the subject is 
withdrawn from the study by the investigator, they will be referred to their Primary Care Manager (PCM) to continue with 
standard of care treatment. 
 
PREGNANCY: Subjects must agree to take precautions to prevent pregnancy during the course of this study due to the possible 
effect MSM may cause an unborn child.  The only completely reliable methods of birth control are total abstinence or surgical 
removal of the uterus.  Other methods, such as the use of condoms, a diaphragm or cervical cap, birth control pills, IUD, or sperm 
killing products are not totally effective in preventing pregnancy.  In addition, women who are breastfeeding may not participate in 
this study. 
 
If a subject unintentionally becomes pregnant, they will be instructed to cease taking their study pills, return their pill bottle and will 
be removed from the study.  
 
DISPOSAL OF STUDY RELATED PILLS:  Subjects will return any remaining study-related pills directly to the Research Coordinator 
or Principal Investigator. The Research Coordinator or Principal Investigator will be responsible for disposing of the study-
related pills. The preferred method of disposal is to have the Pharmacy dispose of them. If the Pharmacy is unable to dispose of 
them, they will provide directions on safe disposal for the Research Coordinator or Principal Investigator to follow. 
 
OTHER: Subjects will take their study pills daily and will be permitted to have the usual medical care for other co-morbid and 
acute conditions if applicable.  Analysis described above using intention-to-treat principles for any missing data will be used (we 
will use the carry-forward method to impute missing data). 
 
The placebo will be a capsule filled with rice flour, which does not increase the risks to subjects. 
 
This study involves the use of an investigational product (IP) called Methylsulfonylmethane (MSM).  This means that the product 
has not been approved by the Food & Drug Administration (FDA) for treating lower back pain.   It is being given in a dose that does 
not increase the risk to the research subjects.  There are no known risks associated with MSM as it is a compound granted GRAS 
(Generally Recognized As Safe) status by the United States Food and Drug Administration (more information can be found at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=582.20). The Sponsor-Investigator will report 
unexpected SAEs associated with the use of the drug to the FDA as specificed at 21 CFR 312.32(c). 
 
3.6.1. Interventions, Observations, or Data Sought:  
We will assess the effect of 6000 mgs of MSM plus standard of care naproxen taken for 12 weeks plus one follow up visit on 
RMDQ, PIQ-6, pain level, comprehensive metabolic panel (CMP) and complete blood count (CBC) will be assessed at 4 week 
intervals. 
 
3.6.2. Data Collection and Processing: 
Data will be collected and recorded in a spreadsheet. At the conclusion of the study, all personally identifying information will be 
removed prior to analysis based on AFI 33-332, “The Air Force Privacy and Civil Liberties Program” and the “National Institute of 
Standards and Technology Special Publication (NIST SP 800-88) for the approved methods to destroy PII”. 
 
3.6.3. Setting: Mike O’Callaghan Military Medical Center at Nellis Air Force Base. 
 
3.6.4. Date(s): June 2014-June 2016 
 
3.6.5. Source of Research Material:  
Source of Research Material per Participant (Procedures) 
# Routine Care 
# Research Driven 
# Total Procedures 
PIQ6 
0 
5 
5 
RMDQ 
0 
5 
5 
Study Diary 
0 
5 
 
5 

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Serum pregnancy test for women of child-bearing potential 
0 
1 
1 
Comprehensive metabolic panel 
0 
5 
5 
Complete Blood Count 
0 
5 
5 
All specimens kept at NELLIS AFB will be handled and disposed of in accordance with federal regulations. 
 
3.6.6. Subjects:  
We will recruit male and female NELLIS AFB DoD beneficiaries between the ages of 18-65 years old with symptoms of lower back 
pain from any of the clinics at the Mike O’Callaghan Military Medical Center at Nellis Air Force Base.  Some subjects may be the 
patients of the PI or AI; however, the PI will have the AI, or Study staffs recruit their patients to prevent any misconception of 
coercion. No special populations (i.e. children, prisoners, pregnant women, mentally disabled persons, or economically or 
educationally disadvantaged persons) will be eligible for this study. 
 
3.6.7. Inclusion/Exclusion Criteria: 
• 
Inclusion: 
o 
DoD beneficiaries between the ages of 18-65 years old. 
o 
Symptoms of Low Back Pain greater than 12 weeks duration. 
o 
Patients with a history of lower back surgery may be included. 
• 
Exclusion: 
o 
DoD beneficiaries less than 18 years old or greater than 65 years old. 
o 
Lower back pain caused by any of the following: 
 Infection 
 Tumor 
 Osteoporosis 
 Ankylosing spondylitis 
 Fracture 
 Deformity 
 Inflammatory process 
 Cauda equina syndrome 
o 
Treated or untreated central nervous system impairment. 
o 
Meeting the criteria for surgery, including: 
 progressive motor deficit 
 sphincter impairment from neurological cause 
 disabling sciatic pain (in the absence of backache) lasting 6 weeks or more that is attributed to a 
compromised nerve root and demonstrated by magnetic resonance imaging or computed tomography 
o 
Oncologic disease during the previous 5 years. 
o 
Unexplained weight loss, fever, or chills. 
o 
Diagnosed upper urinary tract infection within last 28 days. 
o 
Patients identified during standard of care interview to have a history of intravenous drug use. 
o 
Immunocompromised host. 
o 
A severe comorbidity to include:  
 a detriment to the subjects overall well-being (e.g. painful disabling arthritic hip joints) 
 Cirrhosis 
 Ongoing dialysis  
o 
Radiating symptoms to lower extremities (sciatica). 
o 
History of bleeding disorders. 
o 
History of high blood pressure. 
o 
History of heart, kidney, liver or ulcer disease. 
o 
Allergic to analgesics or Non-steroidal anti-inflammatory agents (NSAIDs). 
o 
Pregnant or breastfeeding. 
o 
Initial pain rating of greater than 8/10 on initial intake evaluation 
o 
If the comprehensive metabolic panel is reviewed by the PI, and any of the values are outside a range deemed 
safe for the subject to be included in study. 
o 
If any of these four components of the complete blood count is reviewed by the PI, and any of the values are 
outside a range deemed safe for the subject to be included in study: 
 White blood cell count 
 Hemoglobin 
 Hematocrit 
 Platelets 

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Non-Exempt Human Research Study 
o 
Patients taking any of the following medications are excluded from participating, unless they agree to wash 
out for two weeks prior to entering the study: 
 Muscle relaxers of any type 
 Tramadol 
 Gabapentin 
 Pregabalin 
 Glucosamine 
 Narcotic pain medications 
 Non-steroidal anti-inflammatory agents (NSAIDs) 
* Patients taking naproxen must agree to wash out for two weeks prior to entering the study, but can begin taking it again, as 
prescribed, after Visit 1 where a baseline pain assessment is performed. 
 
3.6.8. Instrumentation: N/A 
 
4.0.  Human Subject Protection: 
 
4.1. Recruitment:  
All potentially eligible patients will be offered an opportunity to participate. Primary Care Managers (PCMs) who are not part of 
the research team will be informed about the study and provided information on the inclusion/exclusion criteria. PCM referrals 
and posted advertisements will be utilized for recruiting subjects to the study. Some patients may be patients of the PI or AI, 
however, they will have the study staff recruit their patients to prevent any misconception of coercion or undue influence. If a 
potential subject is identified by the treating PCM and is interested in obtaining more information about the study, the patient 
will either be provided a contact number to the Research Staff, the Research Staff will be given the potential subject’s contact 
information by the PCM with the patient’s oral or written authorization, or the PCM will come and get the Research Staff to 
speak with the patient directly.  
 
4.2. Consent Processes:  
The PI, AI, or Research Coordinators will obtain Informed Consent on this study.  Informed consent and HIPAA Authorization will 
be sought in advance from each prospective subject.  Informed consent will be appropriately documented.  [32 CFR 219.117]  
After discussion with one of the investigators, the subject will be given the opportunity to consent.  The investigator will provide 
a written copy of the consent form and allow the subject to read it, review it with the subject, and answer questions.  The 
subject may decline to consent, and no pressure will be applied.  If the subject consents to be enrolled in the study, the proper 
signatures will be obtained, and a copy given to the subject. 
 
4.3 Participation Compensation:  Subjects will not be paid for participation in this study. 
 
4.4. Assent Process: N/A 
 
4.5. Benefits:  The benefits to the subjects may include a decrease in lower back pain and increase in function. 
 
4.6. Risks:  Risks to the subject are minimal.  
 
Since the interaction between MSM and the medications in the exclusion list that require a washout period (Muscle relaxers of 
any type, Non-steroidal anti-inflammatory agents (NSAIDs), Tramadol, Gabapentin, Pregabalin, Glucosamine, Narcotic pain 
medications) have not been studied, patients will be asked not to resume taking these medications while participating in this 
study. 
 
Less likely and not serious: 
• 
Risks related to Blood Draws: 
o 
Bleeding 
o 
Feeling light-headed 
o 
Bruising at the blood draw site 
o 
Infection 
• 
Risks related to MSM: 
o 
Bloating 
o 
Constipation 
o 
Indigestion 
o 
Fatigue 

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o 
Decreased concentration 
o 
Insomnia 
o 
Headache 
 
Rare and serious: 
There may be a risk that the subject has an allergy to MSM that they are not aware of currently.  The signs and symptoms of an 
allergic reaction include: 
o 
Shortness of breath 
o 
Hives (itchy rash) 
o 
Runny nose 
o 
Watery eyes 
o 
Sore eyes 
o 
Asthma 
o 
Lip swelling 
o 
Tongue swelling 
o 
Nausea 
o 
Bronchospasm (a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles) 
o 
Anaphylaxis (whole-body allergic reaction that has the following signs and symptoms): 
 
Abdominal pain or cramping 
 
Abnormal (high-pitched) breathing sounds 
 
Anxiety 
 
Confusion 
 
Cough 
 
Diarrhea 
 
Difficulty breathing 
 
Difficulty swallowing 
 
Fainting, light-headedness, dizziness 
 
Hives 
 
Itchiness 
 
Nasal congestion 
 
Nausea, vomiting 
 
Palpitations 
 
Skin redness 
 
Slurred speech 
 
Wheezing 
*If the subject experiences any of these symptoms, they are instructed to stop taking the study pills and seek urgent medical 
treatment. 
 
There is also a potential risk of an inadvertent disclosure of personal health information. 
 
4.7. Costs: N/A 
 
4.8. Safeguards for Protecting Information:  
The research consents will be stored in a locked cabinet in a locked room.  Medical records will be annotated with ICD-10 code 
Z00.6 to reflect the subject’s participation in a research study.All research data including patient demographics will be kept in an 
electronic database, which will be encrypted, double password protected and the access will be restricted.  The research data 
will be de-identified and any links to identifiable data will be destroyed as soon as possible. The research data will not be utilized 
for further research activity beyond the protocol stipulations without additional IRB approval. 
 
4.9. Safeguards for Protecting Subjects:  
The principal investigator will be responsible for the protocol safety monitoring.  The PI will make study documents (e.g., 
consent forms, data pulls) and pertinent hospital or clinical records readily available for inspection by the local IRB and over 
sight staff for confirmation of the study data. 
 
4.9.1. Minimizing Risks:  
If a subject experiences any injury, adverse event, or unexpected clinical finding, a PI, AI, or Primary Care provider will be 
available to assess the subject and initiate proper clinical care 
 

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4.9.2. Vulnerable Populations: N/A 
 
4.9.3. Clinical Care:  
If a subject experiences any injury, adverse event, or unexpected clinical finding, a PI, AI, or Primary Care provider will be 
available to assess the subject and initiate proper clinical care. 
 
4.9.4. Injury Compensation: N/A 
 
4.9.5. Data Safety Monitoring:   
The trial will be conducted in compliance with this protocol, International Conference on Harmonization (ICH) Guidelines for 
Good Clinical Practice (GCP), and any applicable national and international regulatory requirements. The principal and associate 
investigators will be monitoring all aspects of the study in accordance with the appropriate regulations and will have regular 
meetings with periodic quality control of data documentation and collection. The objectives of the monitoring meetings will be: 
1) To verify the prompt reporting of all data points, including reporting Serious Adverse Events (SAEs) and checking 
availability of signed informed consent, 
2) To compare individual subject records, data pulls and/or the study source documents/case report forms (supporting 
data, laboratory specimen records and medical records to include physician progress notes, nurses’ notes, subjects’ 
hospital charts), 
3) To ensure protection of study subjects, compliance with the protocol, and accuracy and completeness of records. 
 
The principal investigator will be responsible for the protocol safety monitoring.  The PI will make study documents (e.g., 
consent forms, data pulls) and pertinent hospital or clinical records readily available for inspection by the local IRB and over 
sight staff for confirmation of the study data. 
 
David Moss, DO, Maj (Primary) and Matthew Hawks, Capt (Alternate) will be the research monitors assigned to this study. 
 
5.0. Alternatives:  The alternative is not to participate in this study. 
 
6.0. Data Analysis:  
 
6.1. Outcome Measures: 
We will be utilizing stratified random sampling with proportionate allocation which will ensure that all parts of the population 
are represented in the sample. 
Factors: 
1. 
Subject Characteristics 
a. Subject identification: nominal variable (1 … n)  
b. Gender: binomial variable (male, female) 
c. 
Age:  interval variable (years) 
d. Height: interval variable (inches) 
e. Weight: interval variable (pounds) 
2. 
Treatment: nominal variable (Naproxen + MSM, Naproxen + placebo) 
3. Time (5 repeated measures for each subject): nominal variable (0wk, 4wk, 8wk, 12wk, 16wk) 
4. Outcomes 
a. VAS: interval variable 72,73 (1-10 cm) 
b.  RMDQ: interval variable (0-11,18, or 24 depending on instrument used) 
c. 
PIQ-6: interval variable (20-80) 
 
6.2. Sample size estimation/power analysis:  
The power for the rANCOVA was assessed using G*Power Version 3.0.10 76 .  The investigators anticipate there will be large 
effect size as determined by a 50% improvement in clinical outcomes. The results shown below indicate 34 subjects per 
Treatment group with 5 repeated measures will achieve a power of 0.80 to detect a large effect size of 0.40 at α = 0.05.  
 
Input: 
 
Effect size f 
= 0.4 
 
β/α ratio 
= 4 
 
Total sample size 
= 68 
 
Number of groups 
= 2 
 
Repetitions 
= 5 

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Corr among rep measures 
= 0.8 
Output: 
 
Critical F 
= 2.524097 
 
Numerator df 
= 4.000000 
 
Denominator df 
= 63.000000 
 
α err prob 
= 0.049538 
 
β err prob 
= 0.198150 
 
Power (1-β err prob) 
= 0.801850 
 
Software R Version 2.13.1 (R Foundation for Statistical Computing) 77 
 
6.3. Statistical Analysis:  
Descriptive statistics: Sample means, standard deviations and standard errors of measurement for interval variables and 
frequency distributions for nominal variables will be calculated for the total sample and for the Treatment groups. 
 
Hypothesis Testing: H01 and H02: interval outcome data will be tested by a mixed effects repeated measures analysis of co-
variance (rANCOVA  
 
Post Hoc Tests: In the event H02 is rejected, contrasts will used to investigate differences among means.   
 
6.4 Number of Subjects:   
Number of subjects planned for NELLIS AFB 
Enrolled in Study   100 
to result in 
68 
completing the study. 
TOTAL NUMBER OF SUBJECTS (nation-wide/study-wide): 100 
 
7. Duration of Study: Approximate duration of the study: 2 years 
 
8.  Local and External Support Services:  None 
 
9.  Intramural (GME) and Extramural Funding Support:   
This study will be sponsored by Bergstrom Nutrition.  The collaborative research will be executed in accordance with 15 USC 
3710a through a Cooperative Research and Development Agreement, between the 99th MDG and Bergstrom Nutrition.   The 
estimated fair market value of the support is $17,570.00. We received a grant from AFMSA/SG5 in the amount of $50,000 in 
support of purchasing supplies and a research coordinator. 
 
10. Conflict of Interest: None 
 
a. Financial Conflict of Interest: No financial conflicts of interest exist. 
 
b. Personal Conflict of Interest: No personal conflicts of interest exist. 
 
c. Current Off-Duty Employment: None 
 
11.  Use of an Investigational New Drug, use of a Drug for a non-FDA approved purpose, use of an investigative device or use of a 
placebo:   
This research uses an Investigational New Drug 
 
 
 
 
 
[x] YES [] NO 
This research uses a FDA approved drug for a non-FDA approved purpose                                                                          [] YES 
[x] NO 
This research uses an Investigational Device       
 
 
 
 
 
[] YES 
[x] NO 
This research uses a placebo. 
 
 
                                                                                    
[x] YES [] NO 
 
12.  Medical Research Area for the Study:  (Pick as many as appropriate) 
[] Analytical Chemistry 
[] Anatomy 
[] Anesthesiology 
[] Biochemistry 
[] Cardiovascular Surgery 
[] Cardiology 
[] Cell Biology 
[] Dentistry 
[] Dermatology 
[] Dietetics 
[] Electrophysiology 
[] Endocrinology 
[] Emergency medicine 
[] Gastroenterology 
[] General Surgery 
[] Hematology 
[] Histology 
[] Immunology/Allergy 
[] Infectious Disease 
[] Microbiology 
[] Molecular Biology 
[] Neonatology 
[] Neurology 
[] Neurosurgery 
[] Nursing 
[] OB/GYN 
[] Occupational Medicine 
[] Occupational Therapy 
[] Oncology 
[] Ophthalmology 
[] Oral/Maxillofacial Surgery 
[] Orthopedics 
[] Pathology 
[] Pediatrics 
[] Pharmacology 
[] Physical Therapy 
[] Mental Health 
[] Radiology/Imaging 
[] Urology 
[] Wellness 
[] Other (state): 
 

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13. Attachments: 
1. 
Certificate of Compliance 
2. 
Informed Consent Document 
3. HIPAA Authorization Document 
4. Use of an Investigational New Drug (IND) in Research 
5. Use of a Placebo in Research 
6. Intramural and Extramural Funding Support Appendix 
7. FDA Correspondence 
8. Pharmacy Letter of Support 
9. Laboratory Letter of Support 
10. Pain Impact Questionnaire 
11. Roland Morris Disability Questionnaire 
12. Study Medication Diary 
13. Form A2-Study Personnel