musculoskeletal disorders of the upper back , shoulders , and neck are common in many occupations that require physical exertion , repetitive movements , static muscle contraction , prolonged sitting before a computer , or maintaining fixed or extreme postures.16 in some instances , muscle fatigue subsequent to overwork or to poor posture results in tension or overactivation of the muscles of the neck.2,5,7,8 work - related neck , shoulder , and upper back musculoskeletal disorders include tension neck syndrome , rotator cuff syndrome , upper back pain , and shoulder tendonitis or tenosynovitis.912 these conditions may cause deterioration of joints , muscles , and soft tissue , persistent pain in related body areas , and disability.6 workplace interventions ( eg , resistance training , stretching exercise programs ) may help to prevent and manage mus - culoskeletal disorders.13 in addition , pharmacologic options , such as acetaminophen and nonsteroidal anti - inflammatory drugs ( nsaids ) , are used to manage musculoskeletal pain , and muscle relaxants may be used to manage muscle pain , stiffness , and spasm.1417 although there are many skeletal muscle relaxants , systemically active products are generally available with prescription and are associated with well - documented adverse effects such as somnolence , dizziness , weakness , and dry mouth.17 guaifenesin , an over - the - counter ( otc ) expectorant , has exhibited a muscle relaxant effect in preclinical studies and in patients with cerebral palsy when used in doses higher than those currently available for otc use.18,19 in other preclinical investigations , guaifenesin has shown modest but significant analgesic and anti - inflammatory effects.20 little is known about the potential mechanism by which guaifenesin produces these effects , but a chemically similar muscle relaxant , mephenesin , has been found to be an antagonist of the excitatory amino acids
n - methyl - d - aspartate ( nmda ) and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ( ampa).18,21 whether a true muscle relaxant effect occurs at otc doses of guaifenesin has not been studied previously .
the primary objective of this proof - of - principle study was to explore the efficacy and safety of 2 otc dose strengths of guaifenesin compared with matched placebos for symptom relief in subjects with acute upper back , neck , or shoulder muscle spasm and pain .
this multicenter , randomized , placebo - controlled , repeat - dose , 4-arm , parallel study was conducted at 4 investigational sites in the united states ( clinicaltrials.gov identifier : nct01562548 ) .
eligible subjects with upper back , neck , or shoulder muscle spasm and pain were randomly assigned in a 2:2:1:1 ratio to receive guaifenesin 600 mg ( a single 600 mg mucinex extended release bi - layer tablet ; reckitt benckiser , parsippany , nj , usa ) , guaifenesin 1200 mg ( two 600 mg mucinex extended release tablets ) , placebo matched to guaifenesin 600 mg ( ie , 1 placebo tablet , hereafter referred to as placebo-600 ) , or placebo matched to guaifenesin 1200 mg ( ie , 2 placebo tablets , hereafter referred to as placebo-1200 ) .
the randomization schedule was generated by the biostatistics department of glaxo - smithkline consumer healthcare ( parsippany , nj , usa ) .
all doses were self - administered twice daily ( bid ) for 7 consecutive days .
subjects recorded the intensity of upper back , neck , or shoulder muscle spasm , stiffness , tension , pain , and discomfort twice daily ( 8 am and 8 pm ) on a diary card , using an 11-point numeric rating scale ( nrs ) for each symptom , with anchors of 0=symptom not present and 10=unbearable symptoms . on days 4 and 7 , investigators telephoned subjects to evaluate muscle relaxation and to perform a global assessment of treatment helpfulness ( gath ) , sleep disturbance ( gasd ) , and headache frequency / intensity ( gahf / gahi ) . at that time
muscle relaxation was scored on a 5-point categorical scale of 0=no relaxation , 1=a little relaxation , 2= fair relaxation , 3=good relaxation , and 4=complete relaxation .
the gath was scored on a scale of 0=poor , 1=fair , 2=good , 3=very good , and 4=excellent .
the gasd , gahf , and gahi recorded whether the symptom had increased , decreased , or remained the same .
the vernon  mior disability questionnaire was originally designed to assess how neck pain affects everyday life with regard to pain intensity , personal care , lifting , reading , headaches , concentration , work , driving , sleeping , and recreation , with each item rated on a 6-point scale , with 1 being no disability and 6 being complete disability . here
, the same questionnaire was used to measure disability resulting from neck , upper back , and shoulder pain .
this study , which was conducted from february 2012 through may 2013 , conformed to the principles of the declaration of helsinki and was approved by an institutional review board ( quorum review , inc , seattle , wa , usa ) .
subjects enrolled in the study were healthy men and women aged 1865 years with a new episode of acute upper back , neck , or shoulder muscle spasm and pain .
inclusion criteria were muscle pain and/or spasm with an onset within 48 hours of randomization and at least 30 days since a previous episode ; symptoms consistent with a clinical diagnosis ; and subject - rated muscle spasm and pain scores of at least 40 mm on a 100 mm visual analog scale .
subjects had to have a normal neurologic evaluation , physical examination , and clinical laboratory test results .
exclusion criteria were current or recent history of neck , back , and/or shoulder injuries ; spinal disk disease ; osteoporosis ; liver and/or kidney disease ; myocardial infarction within 12 months of randomization ; history of upper back pain with active hypersensitive spots ; history of other chronic pain ( eg , headache , osteoarthritis , or lower back pain ) ; and known or suspected intolerance or hypersensitivity to guaifenesin or methocarbamol ( or closely related compounds ) or any other study medication ingredient .
individuals who had used muscle relaxants , narcotics , monoamine oxidase inhibitors , or selegiline within 2 weeks of randomization or who were currently using tricyclic antidepressants , lithium , anticoagulants , or tramadol were ineligible .
additional exclusion criteria were current pregnancy or breastfeeding , drug or alcohol abuse within the previous 2 years , use of an investigational drug or participation in another clinical trial within 30 days prior to randomization , and involvement in a worker s compensation case .
subjects had to agree to refrain from use of analgesics ( including nsaids , with the exception of aspirin 325 mg / day ) , muscle relaxants , physical or massage therapy , acupuncture , and heat and spa treatments for the duration of the study .
the primary efficacy end point was the change in muscle spasm over the 7-day study period , measured as mean change from baseline for both morning and evening spasms in the 11-point nrs scores recorded in the subjects diary cards and averaged over the 7-day treatment period .
secondary efficacy end points included change from baseline in muscle stiffness , tension , pain , discomfort , and relaxation over the 7-day period , measured as mean change from baseline for both morning and evening symptoms on the 11-point nrs scores .
other secondary end points included muscle relaxation scores , as well as scores for gath and the individual vernon  mior disability questionnaire components on days 4 and 7 .
safety assessments included treatment - emergent adverse events ( teaes ) and serious adverse events ( saes ) .
safety was monitored from the start of treatment until 7 days after the last treatment administration , and treatment - related saes were reported from the time of informed consent through all follow - up contact . severity and relationship to treatment were assessed for all teaes . given the proof - of - concept objective , no formal sample size calculations were performed .
a total of 78 subjects ( 26 in each active treatment randomization group and 13 in each placebo randomization group ) were considered sufficient to visualize any directional change in increased efficacy from placebo to lower- and upper - dose guaifenesin groups for muscle spasm , stiffness , tension , pain , discomfort , and relaxation scores .
directional changes in efficacy were based primarily on comparisons of absolute values of means of guaifenesin 1200 mg bid with placebo-1200 and with guaifenesin 600 mg bid .
placebo-600 was not included in these comparisons , as its only purpose was to test the effect of guaifenesin 600 mg bid .
statistical testing to detect significant differences between treatments was exploratory , as no formal sample size calculations were done for this study .
efficacy analyses were conducted on the intent - to - treat ( itt ) population , which was defined as subjects who had received at least 1 dose of study medication and who had at least 1 post - baseline efficacy assessment .
all primary and secondary end points were summarized using descriptive statistics ( mean , standard deviation [ sd ] , minimum , maximum ) in order to provide an absolute comparison between treatments for the purpose of identifying a directional change in efficacy .
in addition , a mixed - model analysis of covariance ( ancova ; proc mixed of sas ) was used to analyze changes from baseline in subject nrs ratings over the 7-day period ( ie , mean of each morning s and evening s changes from baseline on days 17 ) .
a similar mixed model was used to assess mean muscle relaxation and gath scores on days 4 and 7 ( incorporating morning and evening scores ) .
both ancova models included factors for treatment ( fixed effect ) , site ( random effect ) , and baseline assessment of the end point being analyzed as a covariate .
treatment differences were presented with 95% confidence intervals and associated p - values . global assessments ( gasd , gahf , and gahi ) were summarized by percentage of subjects recording that symptoms had increased , decreased , or stayed the same .
no imputation was performed for missing values for any of the assessments , and subjects who dropped out or were excluded were included in all analyses for which they were evaluable .
adverse events were classified using the medical dictionary for drug regulatory activities version 15.1 and summarized using descriptive statistics .
this multicenter , randomized , placebo - controlled , repeat - dose , 4-arm , parallel study was conducted at 4 investigational sites in the united states ( clinicaltrials.gov identifier : nct01562548 ) .
eligible subjects with upper back , neck , or shoulder muscle spasm and pain were randomly assigned in a 2:2:1:1 ratio to receive guaifenesin 600 mg ( a single 600 mg mucinex extended release bi - layer tablet ; reckitt benckiser , parsippany , nj , usa ) , guaifenesin 1200 mg ( two 600 mg mucinex extended release tablets ) , placebo matched to guaifenesin 600 mg ( ie , 1 placebo tablet , hereafter referred to as placebo-600 ) , or placebo matched to guaifenesin 1200 mg ( ie , 2 placebo tablets , hereafter referred to as placebo-1200 ) .
the randomization schedule was generated by the biostatistics department of glaxo - smithkline consumer healthcare ( parsippany , nj , usa ) .
all doses were self - administered twice daily ( bid ) for 7 consecutive days .
subjects recorded the intensity of upper back , neck , or shoulder muscle spasm , stiffness , tension , pain , and discomfort twice daily ( 8 am and 8 pm ) on a diary card , using an 11-point numeric rating scale ( nrs ) for each symptom , with anchors of 0=symptom not present and 10=unbearable symptoms . on days 4 and 7 , investigators telephoned subjects to evaluate muscle relaxation and to perform a global assessment of treatment helpfulness ( gath ) , sleep disturbance ( gasd ) , and headache frequency / intensity ( gahf / gahi ) . at that time
muscle relaxation was scored on a 5-point categorical scale of 0=no relaxation , 1=a little relaxation , 2= fair relaxation , 3=good relaxation , and 4=complete relaxation .
the gath was scored on a scale of 0=poor , 1=fair , 2=good , 3=very good , and 4=excellent .
the gasd , gahf , and gahi recorded whether the symptom had increased , decreased , or remained the same .
the vernon  mior disability questionnaire was originally designed to assess how neck pain affects everyday life with regard to pain intensity , personal care , lifting , reading , headaches , concentration , work , driving , sleeping , and recreation , with each item rated on a 6-point scale , with 1 being no disability and 6 being complete disability . here
, the same questionnaire was used to measure disability resulting from neck , upper back , and shoulder pain .
this study , which was conducted from february 2012 through may 2013 , conformed to the principles of the declaration of helsinki and was approved by an institutional review board ( quorum review , inc , seattle , wa , usa ) .
subjects enrolled in the study were healthy men and women aged 1865 years with a new episode of acute upper back , neck , or shoulder muscle spasm and pain .
inclusion criteria were muscle pain and/or spasm with an onset within 48 hours of randomization and at least 30 days since a previous episode ; symptoms consistent with a clinical diagnosis ; and subject - rated muscle spasm and pain scores of at least 40 mm on a 100 mm visual analog scale .
subjects had to have a normal neurologic evaluation , physical examination , and clinical laboratory test results .
exclusion criteria were current or recent history of neck , back , and/or shoulder injuries ; spinal disk disease ; osteoporosis ; liver and/or kidney disease ; myocardial infarction within 12 months of randomization ; history of upper back pain with active hypersensitive spots ; history of other chronic pain ( eg , headache , osteoarthritis , or lower back pain ) ; and known or suspected intolerance or hypersensitivity to guaifenesin or methocarbamol ( or closely related compounds ) or any other study medication ingredient .
individuals who had used muscle relaxants , narcotics , monoamine oxidase inhibitors , or selegiline within 2 weeks of randomization or who were currently using tricyclic antidepressants , lithium , anticoagulants , or tramadol were ineligible .
additional exclusion criteria were current pregnancy or breastfeeding , drug or alcohol abuse within the previous 2 years , use of an investigational drug or participation in another clinical trial within 30 days prior to randomization , and involvement in a worker s compensation case .
subjects had to agree to refrain from use of analgesics ( including nsaids , with the exception of aspirin 325 mg / day ) , muscle relaxants , physical or massage therapy , acupuncture , and heat and spa treatments for the duration of the study .
the primary efficacy end point was the change in muscle spasm over the 7-day study period , measured as mean change from baseline for both morning and evening spasms in the 11-point nrs scores recorded in the subjects diary cards and averaged over the 7-day treatment period .
secondary efficacy end points included change from baseline in muscle stiffness , tension , pain , discomfort , and relaxation over the 7-day period , measured as mean change from baseline for both morning and evening symptoms on the 11-point nrs scores .
other secondary end points included muscle relaxation scores , as well as scores for gath and the individual vernon  mior disability questionnaire components on days 4 and 7 .
safety assessments included treatment - emergent adverse events ( teaes ) and serious adverse events ( saes ) .
safety was monitored from the start of treatment until 7 days after the last treatment administration , and treatment - related saes were reported from the time of informed consent through all follow - up contact . severity and relationship to treatment were assessed for all teaes .
given the proof - of - concept objective , no formal sample size calculations were performed .
a total of 78 subjects ( 26 in each active treatment randomization group and 13 in each placebo randomization group ) were considered sufficient to visualize any directional change in increased efficacy from placebo to lower- and upper - dose guaifenesin groups for muscle spasm , stiffness , tension , pain , discomfort , and relaxation scores .
directional changes in efficacy were based primarily on comparisons of absolute values of means of guaifenesin 1200 mg bid with placebo-1200 and with guaifenesin 600 mg bid .
placebo-600 was not included in these comparisons , as its only purpose was to test the effect of guaifenesin 600 mg bid .
statistical testing to detect significant differences between treatments was exploratory , as no formal sample size calculations were done for this study .
efficacy analyses were conducted on the intent - to - treat ( itt ) population , which was defined as subjects who had received at least 1 dose of study medication and who had at least 1 post - baseline efficacy assessment .
all primary and secondary end points were summarized using descriptive statistics ( mean , standard deviation [ sd ] , minimum , maximum ) in order to provide an absolute comparison between treatments for the purpose of identifying a directional change in efficacy .
in addition , a mixed - model analysis of covariance ( ancova ; proc mixed of sas ) was used to analyze changes from baseline in subject nrs ratings over the 7-day period ( ie , mean of each morning s and evening s changes from baseline on days 17 ) .
a similar mixed model was used to assess mean muscle relaxation and gath scores on days 4 and 7 ( incorporating morning and evening scores ) .
both ancova models included factors for treatment ( fixed effect ) , site ( random effect ) , and baseline assessment of the end point being analyzed as a covariate .
global assessments ( gasd , gahf , and gahi ) were summarized by percentage of subjects recording that symptoms had increased , decreased , or stayed the same .
no imputation was performed for missing values for any of the assessments , and subjects who dropped out or were excluded were included in all analyses for which they were evaluable .
adverse events were classified using the medical dictionary for drug regulatory activities version 15.1 and summarized using descriptive statistics .
ninety - five people were screened , of whom 79 met the enrollment criteria and were randomly assigned to receive guaifenesin 600 mg bid ( n=25 ) , guaifenesin 1200 mg bid ( n=25 ) , placebo-600 ( n=15 ) , and placebo-1200 ( n=14 ) .
one subject in the guaifenesin 1200 mg bid group was lost to follow - up and did not receive treatment and was excluded from the safety and itt populations .
one subject in the placebo-1200 group was excluded from the itt population because the number of pills returned at the end of the study indicated a much lower adherence to study procedures than that indicated in the subject s diary records .
thus , 78 subjects were included in the safety population and 77 in the itt population .
the overall mean ( sd ) age of randomized subjects was 45.9 ( 11.5 ) years , and slightly more than half of all subjects were males ( 55.1% ) .
most study subjects were white ( 66.7% ) ; the remaining subjects were primarily black ( 32.1% ) .
the demographics of the subjects in the individual treatment arms are shown in table 1 . over the 7-day study period ,
the guaifenesin 1200 mg bid group showed a potential directional change for a greater effect on decreasing muscle spasm compared with its matched placebo and guaifenesin 600 mg bid ( figure 1a ) .
reduction of muscle spasm in subjects treated with guaifenesin 1200 mg bid was 25% greater than that of subjects in the placebo-1200 group and 16% greater than that of subjects in the guaifenesin 600 mg bid group .
guaifenesin 600 mg bid did not show a clear effect on decreasing muscle spasm compared with its matched placebo ( mean change score , 1.53 vs 1.74 ; table 2 ) . over the 7-day study period , treatment with guaifenesin 1200 mg bid provided numerically greater improvements
than its matched placebo and guaifenesin 600 mg bid on most other subject - reported symptoms , including pain ( figure 1b ) , tension ( figure 1c ) , and discomfort .
subjects in the guaifenesin 1200 mg bid group experienced greater mean reductions of 52% and 31% in pain , 28% and 13% in tension , and 108% and 20% in discomfort compared with subjects in the placebo-1200 and guaifenesin 600 mg bid groups , respectively ( table 2 ) .
guaifenesin 600 mg bid did not show a clear effect toward improvement on these outcomes compared with its matched placebo .
improvement in muscle discomfort with guaifenesin 1200 mg bid was significantly greater than placebo-1200 ( p=0.0358 ) .
all other differences among treatments for the above - mentioned end points were not significant ( p>0.05 ; table 2 ) . there was a directional change suggesting increasing effects on muscle relaxation from placebo-1200 to guaifenesin 600 mg bid to guaifenesin 1200 mg bid ( table 3 ) .
mean muscle relaxation on day 4 for subjects in the guaifenesin 1200 mg bid group was 39% and 3% greater than mean muscle relaxation for subjects in the placebo-1200 and guaifenesin 600 mg bid groups , respectively . on day 7 , this directional change continued with a 28% and 17% greater effect of guaifenesin 1200 mg bid over placebo-1200 and guaifenesin 600 mg bid groups , respectively .
guaifenesin 600 mg bid did not produce greater muscle relaxation compared with its matched placebo on both days 4 and 7 ( table 3 ) .
similar results to muscle relaxation were observed for gath ( table 3 ) . on day 4 , subjects rated guaifenesin 1200 mg bid 94% and 10% higher than subjects in the placebo-1200 and guaifenesin 600 mg bid groups , respectively . on day 7 , these values were 23% and 10% , respectively .
the greatest treatment effect for gath and muscle relaxation was observed on day 4 ( table 3 ) .
there was a significant difference between guaifenesin 1200 mg bid and placebo-1200 ( p=0.0211 ) for gath and a borderline significant difference between these 2 groups for muscle relaxation ( p=0.0523 ) .
for example , the effect of guaifenesin 1200 mg bid on muscle relaxation on day 7 was 22% higher than on day 4 .
there were no directional changes in effect with regard to effects on sleep disturbance , headache frequency , or headache intensity based on gasd , gahf , and gahi scores , respectively ( table s1 for day 7 data ) . on day 4
, subjects in the guaifenesin 1200 mg bid group had overall better ( lower ) mean vernon  mior index scores than subjects in the guaifenesin 600 mg bid group , and subjects in the guaifenesin 600 mg bid group had overall better ( lower ) scores than subjects in the placebo-1200 group ( figure 2 ) .
there was a directional change on day 4 of placebo-1200 ( 2.39 ) > guaifenesin 600 mg bid ( 2.31 ) > guaifenesin 1200 mg bid ( 2.01 ) .
there was a reduction of 16% and 13% in the overall mean vernon  mior index for subjects in the guaifenesin 1200 mg bid group compared with subjects in the placebo-1200 and guaifenesin 600 mg bid groups .
a similar directional change was observed on day 7 , where there was a reduction of 10% and 20% in the overall vernon 
mior index of subjects in the guaifenesin 1200 mg bid group compared with the placebo-1200 and guaifenesin 600 mg bid groups , respectively . within each treatment group , vernon  mior disability scores improved noticeably from day 4 to day 7 ( figure 2 ) .
a summary of results for upper back / neck / shoulder pain disability end points is presented in table 4 .
twenty - one teaes were reported by 17 ( 21.8% ) subjects in the study .
eight teaes occurred in 6 subjects ( 25.0% ) in the guaifenesin 1200 mg bid group , 4 teaes in 3 subjects ( 21.4% ) in the placebo-1200 group , 8 teaes in 7 subjects ( 28.0% ) in the guaifenesin 600 mg bid group , and 1 teae in 1 subject ( 6.7% ) in the placebo-600 group .
the most common categories of teaes were nervous system disorders ( eg , headache , dizziness , dysgeusia , and somnolence ) and infections ( eg , upper respiratory infections and nasopharyngitis ) .
nearly all teaes were mild ; there were 2 moderate teaes ( upper respiratory tract infection and hyperhidrosis ) in the guaifenesin 1200 mg bid group , 3 moderate teaes ( headache , sinusitis , and sleep disorder ) in the placebo-1200 group , 2 moderate teaes ( headache and arthralgia ) in the guaifenesin 600 mg bid group , and no moderate teaes in the placebo-600 group .
seven teaes in 7 subjects were considered to be treatment - related , including 1 case of moderate hyperhidrosis in the guaifenesin 1200 mg bid group , 1 moderate headache and 1 moderate sleep disorder in the placebo-1200 group , 1 mild case each of dizziness , dysgeusia , and fatigue in the guaifenesin 600 mg bid group , and 1 case of mild abdominal discomfort in the placebo-600 group .
ninety - five people were screened , of whom 79 met the enrollment criteria and were randomly assigned to receive guaifenesin 600 mg bid ( n=25 ) , guaifenesin 1200 mg bid ( n=25 ) , placebo-600 ( n=15 ) , and placebo-1200 ( n=14 ) .
one subject in the guaifenesin 1200 mg bid group was lost to follow - up and did not receive treatment and was excluded from the safety and itt populations .
one subject in the placebo-1200 group was excluded from the itt population because the number of pills returned at the end of the study indicated a much lower adherence to study procedures than that indicated in the subject s diary records .
thus , 78 subjects were included in the safety population and 77 in the itt population .
the overall mean ( sd ) age of randomized subjects was 45.9 ( 11.5 ) years , and slightly more than half of all subjects were males ( 55.1% ) .
most study subjects were white ( 66.7% ) ; the remaining subjects were primarily black ( 32.1% ) .
the demographics of the subjects in the individual treatment arms are shown in table 1 .
over the 7-day study period , the guaifenesin 1200 mg bid group showed a potential directional change for a greater effect on decreasing muscle spasm compared with its matched placebo and guaifenesin 600 mg bid ( figure 1a ) .
reduction of muscle spasm in subjects treated with guaifenesin 1200 mg bid was 25% greater than that of subjects in the placebo-1200 group and 16% greater than that of subjects in the guaifenesin 600 mg bid group .
guaifenesin 600 mg bid did not show a clear effect on decreasing muscle spasm compared with its matched placebo ( mean change score , 1.53 vs 1.74 ; table 2 ) .
over the 7-day study period , treatment with guaifenesin 1200 mg bid provided numerically greater improvements than its matched placebo and guaifenesin 600 mg bid on most other subject - reported symptoms , including pain ( figure 1b ) , tension ( figure 1c ) , and discomfort .
subjects in the guaifenesin 1200 mg bid group experienced greater mean reductions of 52% and 31% in pain , 28% and 13% in tension , and 108% and 20% in discomfort compared with subjects in the placebo-1200 and guaifenesin 600 mg bid groups , respectively ( table 2 ) .
guaifenesin 600 mg bid did not show a clear effect toward improvement on these outcomes compared with its matched placebo .
improvement in muscle discomfort with guaifenesin 1200 mg bid was significantly greater than placebo-1200 ( p=0.0358 ) .
all other differences among treatments for the above - mentioned end points were not significant ( p>0.05 ; table 2 ) .
there was a directional change suggesting increasing effects on muscle relaxation from placebo-1200 to guaifenesin 600 mg bid to guaifenesin 1200 mg bid ( table 3 ) .
mean muscle relaxation on day 4 for subjects in the guaifenesin 1200 mg bid group was 39% and 3% greater than mean muscle relaxation for subjects in the placebo-1200 and guaifenesin 600 mg bid groups , respectively . on day 7 , this directional change continued with a 28% and 17% greater effect of guaifenesin 1200 mg bid over placebo-1200 and guaifenesin 600 mg bid groups , respectively .
guaifenesin 600 mg bid did not produce greater muscle relaxation compared with its matched placebo on both days 4 and 7 ( table 3 ) .
similar results to muscle relaxation were observed for gath ( table 3 ) . on day 4 , subjects rated guaifenesin 1200 mg bid 94% and 10% higher than subjects in the placebo-1200 and guaifenesin 600 mg bid groups , respectively . on day 7 , these values were 23% and 10% , respectively . the greatest treatment effect for gath and muscle relaxation
there was a significant difference between guaifenesin 1200 mg bid and placebo-1200 ( p=0.0211 ) for gath and a borderline significant difference between these 2 groups for muscle relaxation ( p=0.0523 ) . on day 7 , treatment effect increased compared with day 4 . for example , the effect of guaifenesin 1200 mg bid on muscle relaxation on day 7 was 22% higher than on day 4 .
there were no directional changes in effect with regard to effects on sleep disturbance , headache frequency , or headache intensity based on gasd , gahf , and gahi scores , respectively ( table s1 for day 7 data ) .
on day 4 , subjects in the guaifenesin 1200 mg bid group had overall better ( lower ) mean vernon  mior index scores than subjects in the guaifenesin 600 mg bid group , and subjects in the guaifenesin 600 mg bid group had overall better ( lower ) scores than subjects in the placebo-1200 group ( figure 2 ) .
there was a directional change on day 4 of placebo-1200 ( 2.39 ) > guaifenesin 600 mg bid ( 2.31 ) > guaifenesin 1200 mg bid ( 2.01 ) .
there was a reduction of 16% and 13% in the overall mean vernon  mior index for subjects in the guaifenesin 1200 mg bid group compared with subjects in the placebo-1200 and guaifenesin 600 mg bid groups .
a similar directional change was observed on day 7 , where there was a reduction of 10% and 20% in the overall vernon 
mior index of subjects in the guaifenesin 1200 mg bid group compared with the placebo-1200 and guaifenesin 600 mg bid groups , respectively . within each treatment group , vernon  mior disability scores improved noticeably from day 4 to day 7 ( figure 2 ) .
a summary of results for upper back / neck / shoulder pain disability end points is presented in table 4 .
twenty - one teaes were reported by 17 ( 21.8% ) subjects in the study .
eight teaes occurred in 6 subjects ( 25.0% ) in the guaifenesin 1200 mg bid group , 4 teaes in 3 subjects ( 21.4% ) in the placebo-1200 group , 8 teaes in 7 subjects ( 28.0% ) in the guaifenesin 600 mg bid group , and 1 teae in 1 subject ( 6.7% ) in the placebo-600 group .
the most common categories of teaes were nervous system disorders ( eg , headache , dizziness , dysgeusia , and somnolence ) and infections ( eg , upper respiratory infections and nasopharyngitis ) .
nearly all teaes were mild ; there were 2 moderate teaes ( upper respiratory tract infection and hyperhidrosis ) in the guaifenesin 1200 mg bid group , 3 moderate teaes ( headache , sinusitis , and sleep disorder ) in the placebo-1200 group , 2 moderate teaes ( headache and arthralgia ) in the guaifenesin 600 mg bid group , and no moderate teaes in the placebo-600 group .
seven teaes in 7 subjects were considered to be treatment - related , including 1 case of moderate hyperhidrosis in the guaifenesin 1200 mg bid group , 1 moderate headache and 1 moderate sleep disorder in the placebo-1200 group , 1 mild case each of dizziness , dysgeusia , and fatigue in the guaifenesin 600 mg bid group , and 1 case of mild abdominal discomfort in the placebo-600 group .
this is the first study to evaluate guaifenesin for managing symptoms of upper back , neck , and shoulder pain .
the results suggest further investigation of the potential of guaifenesin 1200 mg bid to provide some relief in muscle spasm , pain , tension , and discomfort of the upper back , neck , and shoulders is warranted .
the reduction in muscle discomfort with guaifenesin 1200 mg compared with placebo-1200 was statistically significant ( p=0.0358 ) ; the rest of these improvements were not significant ( p>0.05 ) ; it is noted that in this small proof - of - principle study , analyses were not powered for pre - specified statistical testing between treatments .
the 1200 mg bid dose of guaifenesin suggested a potential for therapeutic muscle relaxant effect .
however , any observed differences between treatments diminished over the course of the study , possibly due to the natural course of upper back pain / muscle spasm , which is generally a self - limiting disorder such that patients may have recovered at day 7 .
this suggests that future studies should focus on earlier ( eg , day 4 ) outcomes . the directional change in effect observed for upper back / neck / shoulder pain disability on the vernon  mior questionnaire end points was consistent with that of most of the other end points in the study .
subjects in the guaifenesin 1200 mg bid group had better ( lower ) overall scores than subjects in the guaifenesin 600 mg bid group , and subjects in the guaifenesin 600 mg bid group had better ( lower ) scores than subjects in the placebo-1200 group .
this study adds support to the limited evidence suggesting that guaifenesin has muscle relaxant activity.19 in an earlier small , exploratory clinical study , guaifenesin at doses up to 220.5 mg / kg ( 100 mg / lb ) of body weight showed muscle relaxant and antispasmodic effects in children with athetoid or tonic spasticity ( n=18).19 methocarbamol , a car - bamate derivative of guaifenesin , also has muscle relaxant properties22,23 and is prescribed for the relief of discomfort associated with acute , painful musculoskeletal conditions.24 based on these prior studies , muscle spasm was selected as the primary outcome for our investigation ; however , results of the secondary end points showed the largest treatment effect for guaifenesin 1200 mg bid vs placebo-1200 on muscle pain and discomfort .
therefore , pain and discomfort may be more appropriate primary end points in future studies .
acute , non - traumatic back , shoulder , and neck pain may be self - limiting and , for most patients , may improve or resolve within several days of onset without intervention ; however , the pain sometimes persists or recurs and converts to a chronic condition lasting months or even years.2527 the availability of an otc muscle relaxant may provide timely access to an effective remedy for relief of acute symptoms .
while none of the directional changes in effect observed in the primary and secondary outcomes achieved statistical significance , it should be noted that this was a small , proof - of - principle study for which sample size was not powered to show statistical difference between active treatments and their matched placebos .
furthermore , the 2:2:1:1 randomization ratio led to only 15 subjects assigned to placebo-600 and 14 assigned to placebo-1200 ; the small numbers of subjects may have contributed to the higher than expected placebo response in the placebo-600 group due to sampling bias and the possibility that the subjects were not representative of the general population experiencing upper back , neck , and shoulder pain .
nonetheless , this study has provided interesting preliminary evidence on another potential therapeutic use for otc guaifen - esin .
therefore , a larger , adequately powered study is warranted to further investigate the potential muscle relaxant and pain reduction effects of guaifenesin 1200 mg bid .
results from this proof - of - principle study showed a directional change in benefit from placebo to lower and upper doses of guaifenesin for muscle spasm , pain , tension , discomfort , and relaxation , suggesting that the otc dose of guaifenesin 1200 mg bid may potentially provide symptom relief from upper back , neck , and shoulder musculoskeletal pain and discomfort .
gasd , gahf , and gahi at day 7 ( itt population ) notes : bid , twice daily ; placebo-600 , placebo matched to guaifenesin 600 mg bid ; placebo-1200 , placebo matched to guaifenesin 1200 mg bid .
abbreviations : gasd , global assessment of sleep disturbance ; gahf , global assessment of headache frequency ; gahi , global assessment of headache intensity ; itt , intent - to - treat .
 background / objectiveguaifenesin , an over - the - counter ( otc ) expectorant , has exhibited muscle relaxant effects preclinically and clinically . 
 this proof - of - principle study explored whether otc doses of guaifenesin can provide relief from acute upper back , neck , or shoulder muscle spasm and pain.methodsthis multicenter , placebo - controlled , repeat - dose , parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back , neck , or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily ( bid ) in a 2:2:1:1 ratio for 7 days . 
 the primary end point was the change from baseline in muscle spasm relief , measured using an 11-point numeric rating scale ( 0=not present to 10=unbearable ) recorded twice daily and averaged over the 7-day treatment period . 
 analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect.resultsa total of 77 subjects were included in the 4 treatment groups . 
 least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg , 1.42 with its matched placebo , 1.53 with guaifenesin 600 mg , and 1.74 with its matched placebo . 
 treatment with guaifenesin 1200 mg bid provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg bid . 
 these differences were not statistically significant . based on comparisons of absolute mean values , a consistent directional change in effect 
 was observed , suggesting some benefit from placebo to lower - to - upper doses of guaifenesin with regard to muscle spasm , tension , pain , discomfort , and relaxation . 
 no severe or serious adverse events were reported.conclusionresults suggest the potential for otc dose of guaifenesin 1200 mg bid to provide symptomatic relief of upper back musculoskeletal pain and spasm . 
 confirmation of this preliminary result in a larger , adequately powered study is needed . 