What is the safety and efficacy with the use of carisoprodol?

Comment by InpharmD Researcher

Carisoprodol is an oral skeletal muscle relaxant that has a barbiturate-like active metabolite. Studies show varying results when compared to other skeletal muscle relaxants and a higher risk of sedation than placebo. Because of the barbiturate-like effects of carisoprodol, it is a controlled substance and not routinely recommended by guidelines.

All
Background

Carisoprodol is an oral, central-acting, skeletal muscle relaxant used to treat acute musculoskeletal pain, especially acute low back pain, for short durations of up to two or three weeks. Its exact mechanism of action is not fully understood but is thought to involve CNS depression through alterations in neuronal communication within the reticular formation and spinal cord, primarily leading to sedation rather than direct muscle relaxation. Carisoprodol is metabolized to meprobamate, which produces sedative and anxiolytic effects by binding to barbiturate receptor binding sites. The metabolism involves the CYP2C19 enzyme, raising concerns about genetic polymorphisms that may affect drug concentration. Despite these concerns, studies have not associated these genetic variants with an increased risk of mortality from carisoprodol toxicity. [1]

Carisoprodol is available in 250 mg and 350 mg tablets, recommended to be taken three times daily and at bedtime. The drug has an onset of action of about 30 minutes, with effects lasting 4 to 6 hours. Caution is advised for patients with renal or hepatic dysfunction due to the lack of data on proper dosing in these populations. Common side effects include dizziness, drowsiness, and headache. Because of these side effects, particularly the risks associated with CNS depression, carisoprodol is listed on the Beers list, indicating it may be inappropriate for older adults due to the higher risk of side effects outweighing potential benefits. [1]

Comparative studies with other muscle relaxants, such as diazepam and cyclobenzaprine, showed varying results, with some indicating similar effectiveness in pain improvement. The abuse potential of carisoprodol is a significant concern, given its capability to modulate GABAa function and the abuse and dependence risks associated with its active metabolite, meprobamate. Chronic use can lead to withdrawal symptoms upon discontinuation and enhanced CNS depression, particularly in elderly patients and those with renal insufficiency. [1]

The American Pain Society and the American College of Physicians recommend acetaminophen or NSAIDs as first-line treatment for most patients due to their favorable side-effect profile. Following the failure of first-line treatment, skeletal muscle relaxants, benzodiazepines, and opioids may be considered for additional pain relief despite the controversies regarding muscle relaxants' efficacy, adverse effects, and increased cost. Guidelines from Veterans Affairs do not routinely support carisoprodol use, even though they acknowledge it can be helpful short term. Trials that included carisoprodol were associated with an increased risk of sedation and dizziness versus placebo; additionally, the risk of dependence leads to it not being recommended for acute or chronic low back pain by Veterans Affairs. [2], [3]

References:

[1] Witenko C, Moorman-Li R, Motycka C, et al. Considerations for the appropriate use of skeletal muscle relaxants for the management of acute low back pain. P T. 2014;39(6):427-435.
[2] Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society [published correction appears in Ann Intern Med. 2008 Feb 5;148(3):247-8. doi: 10.7326/0003-4819-148-3-200802050-00020]. Ann Intern Med. 2007;147(7):478-491. doi:10.7326/0003-4819-147-7-200710020-00006
static/file/VADoDLBPCPGFinal508
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the safety and efficacy with the use of carisoprodol?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Tables 1-6 for your response.
  Table 1

 

Meta-analyses Assessing Carisoprodol versus other Skeletal Muscle Relaxants in Treating Low Back Pain 

Citation

Design/Intervention

Results

 Conclusions

van Tulder et al., 20031

 

Muscle relaxants vs. placebo

 Meta-analysis; Cochrane review

 

N= 30 randomized and/or double-blinded controlled trials, involving patients diagnosed with non-specific low back pain, treated with muscle relaxants as monotherapy or in combination with other therapeutic modalities

 Main results:
  • Pain relief at 2-4 days (non-benzodiazepine muscle relaxant vs. placebo): RR 0.80 (95% CI 0.71 to 0.89)
  • Global efficacy (muscle relaxant vs. placebo): RR 0.49 (95% CI 0.25 to 0.95)
  • AEs (muscle relaxant vs. placebo): RR 1.5 (95% CI 1.14 to 1.98)

 

Comparative results between skeletal muscle relaxants:

  • Carisoprodol vs cyclobenzaprine-hydrochloride: No statistically significant difference in effectiveness for acute low-back pain (based on 1 small high quality trial)

Authors’ Conclusions:

Muscle relaxants are effective in the management of non‐specific low back pain, but the adverse effects require that they be used with caution. Trials are needed that evaluate if muscle relaxants are more effective than analgesics or non‐steroidal anti‐inflammatory drugs.

 

Critique:

Comparative results between skeletal muscle relaxants:

This meta-analysis identified few directly comparative trials of muscle relaxants, and while the identified trials did not find significant differences in effectiveness, their sample sizes may have been too small to reliably detect significant differences between the drug products. Differences in safety outcomes did not appear to have been assessed.

 

Main results:

Some of the included studies were of lower quality due to aspects such as lack of adequate blinding, failing to evaluate treatment compliance, and inadequate methods of randomization.

Wewege et al., 20232

 

Analgesic medicines vs. placebo, or no treatment

 

  

Systematic review and network meta-analysis

 

N= 98 RCTs (15 ,134 patients) including 69 different medicines or combinations: analgesic medicines

(non-steroidal anti-inflammatory drugs, paracetamol, opioids, anti-convulsant drugs, skeletal muscle relaxants, or corticosteroids) compared with another analgesic medicine, placebo, or no treatment in adults (≥18 years) who reported acute non-specific low back pain (for less than six weeks).

Treatment duration ranged from one day (single administration) to 42 days.		  

Main results:

  • Low confidence data suggested that tolperisone is superior to carisoprodol at reducing pain intensity: mean difference -13.7, (95% CI -24.9 to -2.5).
  • Non-benzodiazepine antispasmodic (mean difference -14.3 [95% CI -18.8 to -9.7], very low confidence), nonselective non-steroidal anti-inflammatory drugs plus non-benzodiazepine antispasmodic (-12.7 [95% CI -17.9 to -7.5], very low confidence), non-selective non-steroidal anti-inflammatory drugs plus antispastic (-13.1 [95% CI -25.5 to -0.7], low confidence) might be associated with the moderate reductions in pain intensity compared with placebo.

 

Comparative results between skeletal muscle relaxants, Mean difference (95% CI):

 

Effectiveness in reducing pain vs placebo:

 

Cyclobenzaprine: -16.7 (-29.4 to -3.9) (Very low confidence);

Carisoprodol: -12.4 (-20.3 to -4.6) (Very low confidence);

Chlorzoxazone: -11.3 (-36 to +13.4) [p= NS] (Very low confidence);

Tizanidine:-6.3 (-13.6 to +0.9) [p= NS] (Very low confidence);

Baclofen + ibuprofen: -5.1 (-17.6 to +7.5) [p= NS] (Very low confidence)

Ibuprofen: -4 (-9.5 to +1.4) [p= NS] (Very low confidence)

 

Safety (95% CI): Any adverse event, RR vs placebo:

  • Data were insufficient for analysis of carisoprodol.
 Authors’ Conclusions:

The comparative effectiveness and safety of analgesic medicines for acute non-specific low back pain are uncertain. Until higher quality randomized controlled trials of head-to-head comparisons are published, clinicians and patients are recommended to take a cautious approach to manage acute non-specific low back pain with analgesic medicines.

 

Critique:

Comparative results between skeletal muscle relaxants: Few directly comparative trials were included in this analysis, and as the dosing regimens assessed were not specified they may not have been equivalent, potentially reducing the reliability of the comparative results between skeletal muscle relaxant agents. Dantrolene did not appear to have been included in search criteria for this analysis, obstructing comparative inferences for dantrolene vs other muscle relaxants based on these results.

The assessed effectiveness data may be inadequate to reliably infer comparative effectiveness, as confidence was very low among all agents’ respective results vs placebo.

The safety of each agent, as assessed by the relative risk of any adverse event, were similar to placebo and may be most reliable, given a moderate level of confidence for the regimens: baclofen + ibuprofen, metaxalone + ibuprofen, and ibuprofen monotherapy.

 

Main results:

Many included studies had concerns regarding bias, and missing ata required imputation for continuous outcomes. 

Abbreviations:

AE= adverse event; CI= Confidence Interval; NS= not statistically significant; RCT= randomized controlled trial; RR= relative risk
References:

[1] van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev. 2003;2003(2):CD004252. doi:10.1002/14651858.CD004252
[2] Wewege MA, Bagg MK, Jones MD, et al. Comparative effectiveness and safety of analgesic medicines for adults with acute non-specific low back pain: systematic review and network meta-analysis. BMJ. 2023;380:e072962. Published 2023 Mar 22. doi:10.1136/bmj-2022-072962
  Table 2

 

Randomized, double-blind trial of carisoprodol 250 mg compared with placebo and carisoprodol 350 mg for the treatment of low back spasm

Design

Randomized, double-blind, placebo-controlled, parallel-group, multicenter trial;

N= 828

Objective

To compare the efficacy and safety of carisoprodol 250 mg and 350 mg tablets taken four times daily with placebo in patients with acute, painful musculoskeletal spasm of the lower back

Study Groups

Carisoprodol 250 mg (n= 271);

Carisoprodol 350 mg (n= 281);

Placebo (n= 276)

Inclusion Criteria

18-65 years old; in general good health; and experiencing moderate to severe back spasm

Exclusion Criteria

Duration of back symptoms >3 days; Sciatic pain or Neurologic signs (numbness, tingling, foot drop) or Abnormal lower-extremity strength, sensation, or reflexes; History of spinal pathology; History of osteoporosis or on systemic steroids; Underlying rheumatologic diseases; Body mass index (BMI) >39 kg/m2

Methods

Patients were randomized to receive carisoprodol 250 mg, carisoprodol 350 mg, or placebo tablets three times daily and at bedtime for up to 7 days. Efficacy evaluations included patient-rated relief from backache and global impression of change.

The Roland-Morris Disability Questionnaire (RMDQ) is a 24-item, self-reported disability scale that measures daily function in completing activities affected by back pain.

Duration

1 week

Outcome Measures

Primary: Patient-rated relief from starting backache and global impression of change on treatment day 3

Secondary: RMDQ; patient-rated medication helpfulness; time to symptom improvement; and physician-assessed range of motion

Baseline Characteristics

  

Carisoprodol 250 mg

(n= 264)

Carisoprodol 350 mg

(n= 273)

Placebo

(n= 269)

  

Age, years

 40.9 ± 11.7 40.5 ± 12.4 40.7 ± 13.1  

Female

52.3% 55.7% 60.6%  

Caucasian

 72.3% 76.2% 69.6%  

Non-Hispanic

 69.7% 75.5% 75.8%  

Onset of lower-back pain, days

 1.60 ± 0.75 1.65 ± 0.7 1.62 ± 0.73  

Lower-back pain severity

Moderate

Severe

 

65.5%

34.5%

 

65.9%

34.1%

 

62.8%

37.2%

  

RMDQ score

 11.5 ± 5.3 11.8 ± 5.3 11.2 ± 5.6  

Range of motion, cm

 6.6 ± 3.3 6.4 ± 3 6.6 ± 3.2  

Carisoprodol daily dose, mean (range)

 867.4 mg (0 to 1000 mg) 1196.0 mg (350 to 1400 mg) N/A  

Took study drug for 4-7 days

 69.7% 66.3% 64.5%  

Results

Endpoint

Carisoprodol 250 mg

(n= 264)

Carisoprodol 350 mg

(n= 273)

  

Placebo

(n= 269)

p-Value

 RMDQ score, Mean difference vs placebo (95% Confidence Interval) 

Day 3

Day 7

 

1 (0.29 to 1.72)

1.1 (0.25 to 1.91)

 

1 (0.27 to 1.68)

1.3 (0.50 to 2.14)

 

N/A

N/A

 

N/A

N/A
Time to moderate or marked symptom improvement based on global impression of change, median days 4  4  5  <0.003 

Treatment-emergent adverse events

Drowsiness

Dizziness

Headache

Nausea

 

12.2%

5.9%

5.9%

1.5%

 

16.1%

6.8%

3.2%

4.3%

 

6.5%

0.7%

2.5%

2.5%

 N/A

Study Discontinuations

9.6% (n= 26)

15% (n= 42)

17.4% (n= 48)

 N/A

Serious Adverse Events

0

0

0

 N/A

Primary outcomes: Carisoprodol 250 mg was significantly more effective than placebo for both primary endpoints (p< 0.005). No significant difference was found between the 250 mg and 350 mg doses.

Secondary outcomes not listed above: Treatment with carisoprodol 250- or 350-mg tablets did not significantly increase physician-assessed range of motion on day 3 or 7. Patient-rated medication helpfulness was significantly (p< 0.0001) higher for both doses compared to placebo on day 3 and day 7.

Study Author Conclusions

In conclusion, carisoprodol 250 mg three times daily and at bedtime is effective and well-tolerated for patients with painful, acute musculoskeletal spasm. Patients returned to better functional status, based on the RMDQ, faster with both dosages of carisoprodol than with placebo. The efficacy of carisoprodol 250 mg was comparable to carisoprodol 350 mg with better tolerability, including less drowsiness and fewer discontinuations due to adverse events. The efficacy of carisoprodol was not dependent on a sedative effect; patients improved whether or not they reported sedation.

InpharmD Researcher Critique

The short study duration (1 week) and the lack of an active comparator limit the potential clinical inferences that can be drawn from these results. 



References:

Serfer GT, Wheeler WJ, Sacks HJ. Randomized, double-blind trial of carisoprodol 250 mg compared with placebo and carisoprodol 350 mg for the treatment of low back spasm. Curr Med Res Opin. 2010;26(1):91-99. doi:10.1185/03007990903382428
  Table 3

 

Double-blind, Placebo Controlled Trial of Carisoprodol 250-mg Tablets in the Treatment of Acute Lower-back Spasm

Design

Prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter (49 sites in the United States) trial;

N= 561

Objective

The objective of this placebo-controlled trial was to determine the efficacy and safety of carisoprodol (Soma, MedPointe Pharmaceuticals, Somerset, NJ, USA), a centrally acting skeletal muscle relaxant used to treat acute, painful musculoskeletal conditions, at a dosage of 250 mg three times daily and at bedtime in patients with acute, painful muscle spasm of the lower back.

Study Groups

Carisoprodol 250 mg (n= 277)

Placebo (n= 285)

Inclusion Criteria

 Patients 18-65 years-old; moderate-to-severe lower back muscle spasm and backache; generally good health

Exclusion Criteria

Back symptom duration >3 days; sciatic pain or any neurologic signs or abnormal lower-extremity strength, reflexes or sensory function; positive straight leg raise test; history of spinal pathology; osteoporosis; rheumatologic diseases; BMI >39 kg/m²

Methods

Patients were randomly assigned to receive either carisoprodol 250 mg or a placebo. They recorded their ratings of back pain and global impression of change in diaries. Secondary measures included the Roland-Morris Disability Questionnaire (RMDQ), time to symptom improvement, patient-rated medication helpfulness, and physician assessment of range of motion. Doses were taken three times daily and at bedtime.

Patient-rated relief from starting backache: Patients used diary cards to record the degree of relief with study medication at 12-h intervals (Complete relief= 4, a lot of relief= 3, some relief= 2, a little relief= 1, no relief= 0)

Patient-rated global impression of change: Patient was asked: 'Compared with how you felt before starting study medication, and regardless of whether you think the change was due to medicine, please indicate if you have experienced; completed at 12-h intervals (Marked improvement= 4, moderate improvement= 3, mild improvement= 2, no change= 1, worsening= 0)

Patient-rated medication helpfulness: Patients were asked at baseline, Day 3, Day 7: 'How would you rate this study medication in improving your condition?" (Excellent= 4, very good= 3, good= 2, fair= 1, poor= 0)

Time to symptom improvement: First time there was an assessment of 3 (moderate improvement) or 4 (marked improvement) in the patient's rating of global impression of change

Duration

Intervention: 7 days

Study period: August 11, 2005 through June 8, 2006

Outcome Measures

Primary outcomes: patient-rated global impression of change at day 3 and patient-rated relief from starting backache at day 3

Secondary outcomes: RMDQ scores; patient-rated medication helpfulness; time to symptom improvement; and range of motion

Baseline Characteristics

  

Carisoprodol, 250 mg

(n= 269)

Placebo

(n=278)

  

Age, years

 39.3 ± 11.82 41.5 ± 11.7  

Female

48.7% 55%  

Caucasian

 74% 77.3%  

Non-Hispanic

 63.6% 65.1%  

Onset of lower-back symptoms, days

 1.68 ± 0.78 1.73 ± 0.79  

Lower back pain severity:

Moderate

Severe

 

74.3%

25.3%

 

73.7%

25.9%

  

RMDQ score

10.4 ± 4.9

10.3 ± 5.0

  

Range of motion, cm

6.3 ± 3

5.9 ± 2.8

  

 

Results

Endpoint

Carisoprodol 250 mg

(n= 277)

Placebo

(n= 285)

p-Value

Global impression of change: Moderate or marked improvement at:

Day 2

Day 3

Day 7

 

(Undisclosed)

39%

(Undisclosed)

 

(Undisclosed)

19%

(Undisclosed)

 

p< 0.0001

p< 0.0001

p< 0.0001

Patient-rated relief from starting backache: Moderate or marked improvement at:

Day 2

Day 3

Day 7

 

(Undisclosed)

41%

(Undisclosed)

 

(Undisclosed)

21%

(Undisclosed)

 

p< 0.0001

p< 0.0001

p< 0.0001

Patient-rated medication helpfulness: good or excellent at:

Day 3

Day 7

 

23%

(Undisclosed)

 

11%

(Undisclosed)

 

<0.0001

<0.0001

RMDQ score

Day 3

Day 7

 

6.9

4.1

 

8.7

6.2

 

<0.0001

<0.0001

Moderate to marked symptom improvement

73.2%

53.6%

<0.0001

Time to symptom improvement, median days

3

6

<0.0001

Range of motion, cm at:

Day 3

Day 7

 

7.25

8.2

 

6.69

7.68

 

0.119

0.074

Treatment-emergent adverse events* occurring in ≥ 3% of patients in either treatment group

Drowsiness/Sedation

Dizziness

Headache

 

13.4%

9.7%

3.6%

 

4.6%

3.2%

1.4%

 N/A

Serious adverse events

0

0

 N/A

Study discontinuations

11.2%

13.2%

 N/A

Study Author Conclusions

In this study, patients with acute muscle spasm of the lower back had significantly greater and more rapid relief from starting backache, and had improved functional status, as measured by the RMDQ, during treatment with carisoprodol 250-mg tablets compared to placebo.

InpharmD Researcher Critique

The short study duration (1 week) and the lack of an active comparator limit the potential clinical inferences that can be drawn from these results. 



References:

Ralph L, Look M, Wheeler W, Sacks H. Double-blind, placebo-controlled trial of carisoprodol 250-mg tablets in the treatment of acute lower-back spasm. Curr Med Res Opin. 2008;24(2):551-558. doi:10.1185/030079908x261014
  Table 4

 

Risk of Injury Associated with Skeletal Muscle Relaxant Use in Older Adults

Design

Observational population-based retrospective analysis;

N= 132,277 (All cases and controls who were taking skeletal muscle relaxants: N= 1,166)

Objective

The study aimed to investigate the relationship between the use of skeletal muscle relaxants and the subsequent risk of injury in older adults.

Study Groups

Cases (those with documented injuries) (n= 27,974)

Controls (those without injuries) (n= 104,303)

Inclusion Criteria

Participants enrolled in the health system, aged 65 or older (and cases were alive on the index date of injury); health record data from January 2009 through December 2010

Exclusion Criteria

Resided in long-term care facilities or nursing homes before the index date

Methods

Cases and controls were selected from a base population of older adults, which were then analyzed to segregate data for cases and controls who also were taking skeletal muscle relaxants. Skeletal muscle relaxant exposure was assessed for within 60 days prior to the injury date using prescription records. Conditional logistic regression was used to adjust for various covariates, and risk estimates were presented as odds ratios.

The resulting adjusted odds ratios were adjusted based on age, sex, previous injury, Diagnostic Cost Groups comorbidity score, medications, and concomitant diseases.

Duration

Health record data interval assessed: January 2009 through December 2010

Outcome Measures

Primary outcome: the incidence of injury resulting in hospitalization or emergency/urgent care visits among older adults using skeletal muscle relaxants compared to non-users

Baseline Characteristics

  

Cases

(n= 27,974)

Controls

(n= 104,303)

  

Age, years

 75.5 ±7.5 75.4 ±7.4  

Women

 61.3% 61.5%  

DxCG score

 1.14 ±1.33 0.80 ±1.01  

Skeletal muscle relaxant

Carisoprodol

Cyclobenzaprine

Methocarbamol

 

7.4% (n= 27)

53.2% (n= 194)

38.9% (n= 142)

 

4.9% (n= 39)

57.2% (n= 458)

37.5% (n= 300)

  

Other medications

Antihypertensives

Antidepressants

Opioids

 

52.2%

26.9%

35.3%

 

48.5%

17.5%

26.3%

  

Results

Endpoint

All cases and controls who were taking skeletal muscle relaxants

N= 1,166

p-Value
 

Risk of injury with use of skeletal muscle relaxants vs no use, unadjusted odds ratio (OR) [95% confidence interval (CI)]:

All skeletal muscle relaxants

Carisoprodol

Cyclobenzaprine

Methocarbamol

 

1.73 [1.52 to 1.96]

2.53 [1.54 to 4.15]

1.6 [1.35 to 1.9]

1.79 [1.46 to 2.2]

  

<0.001

0.036

0.029

0.001

Risk of injury with use of skeletal muscle relaxants vs no use, adjusted OR [95% CI]:

All skeletal muscle relaxants

Carisoprodol

Cyclobenzaprine

Methocarbamol

  

1.32 [1.16 to 1.5]

1.73 [1.04 to 2.88]

1.22 [1.02 to 1.45]

1.42 [1.16 to 1.75]

 

<0.001

0.036

0.029

0.001

Study Author Conclusions

In this study, the use of skeletal muscle relaxants was associated with an increased risk of injury among older adults. Through multiple risk factor reduction interventions, falls and injuries can be prevented in community-dwelling older adults. One of the critical strategies for preventing these potentially fatal events includes stopping the use of high-risk medications such as skeletal muscle relaxants.

InpharmD Researcher Critique

All analyzed skeletal muscle relaxants were found to significantly increase the risk of injury in the observed patient population. However, as the carisoprodol results were derived from only 27 cases (compared to 194 cyclobenzaprine cases and 142 methocarbamol cases) and the confidence interval for risk of injury with carisoprodol nearly crossed 1 in the adjusted OR analysis, which would represent a non-statistically significant difference versus no skeletal muscle relaxant use, it is possible that these results may not reliably represent carisoprodol in this population.



References:

Spence MM, Shin PJ, Lee EA, Gibbs NE. Risk of injury associated with skeletal muscle relaxant use in older adults. Ann Pharmacother. 2013;47(7-8):993-998. doi:10.1345/aph.1R735
  Table 5

 

Subjective and Psychomotor Effects of Carisoprodol in Combination With Oxycodone in Healthy Volunteers

Design

Prospective, double-blind, randomized, placebo-controlled, triple-dummy, crossover trial;

N= 15

Objective

The study aimed to investigate the combined effects of carisoprodol and oxycodone on subjective measures of abuse liability and psychomotor performance in healthy volunteers.

Study Groups

Healthy volunteers (N= 15)

Inclusion Criteria

Healthy volunteers; 21-39 years-old; have a high school diploma or equivalent; speak English fluently; and consume alcohol at some level

Exclusion Criteria

Total drug abstention; history of psychiatric or substance use disorders; and any significant medical conditions

Methods

All subjects were treated at different cross-over intervals with: placebo vs carisoprodol 350 mg vs oxycodone 10 mg vs carisoprodol 350 mg followed at 60 minutes by oxycodone 10 mg.

Subjective effects were measured using various questionnaires and scales, while psychomotor performance was evaluated using the Digit Symbol Substitution Test, logical reasoning test, auditory reaction time test, eye-hand coordination test, and a memory recall test.

Duration

Intervention: The study sessions were conducted over a period from 0800 to 1545 hours, with each session being at least one week apart.

Outcome Measures

Primary outcomes: subjective measures (like feelings of euphoria and drug liking) and psychomotor performance

Secondary outcomes: physiological parameters (ex: pupil size)

Baseline Characteristics

 The 15 participants (8 males and 7 females) had a mean age of 27 years. All consumed alcohol (mean 2.8 drinks per week), 3 smoked tobacco, and 5 used marijuana.

Results

The combination of carisoprodol and oxycodone generated significantly greater subjective and psychomotor impairment effects compared to either drug alone. Specific subjective effects included increased feelings of euphoria and drug liking, while psychomotor performance declined as measured by reaction time and logical reasoning tests.

Study Author Conclusions

This is the first study that we are aware of that has shown that carisoprodol and oxycodone, two drugs that are sometimes co-prescribed for relief of pain, produce effects when administered “together” (i.e., separated by 60 min) that are of greater magnitude than when they are administered alone. Some of the effects were not benign, and are of concern from both abuse liability and public safety standpoints.

InpharmD Researcher Critique

Clinical inferences that can be derived from these results are limited by the use of a healthy volunteer population and the short duration of the interventions (1 administration session for each intervention cross-over).



References:

Zacny JP, Paice JA, Coalson DW. Subjective and psychomotor effects of carisoprodol in combination with oxycodone in healthy volunteers. Drug Alcohol Depend. 2012;120(1-3):229-232. doi:10.1016/j.drugalcdep.2011.07.006

  Table 6

Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants
Design

Retrospective, database review

N= 9 cohorts
Objective

To compare the injury rates associated with different skeletal muscle relaxants (SMRs) when used concurrently with the three most commonly dispensed opioids—hydrocodone, oxycodone, and tramadol—and to determine if the risk varies by specific SMR and order of initiation
Inclusion Criteria

Adult Medicaid beneficiaries from California, Florida, New York, and Pennsylvania, with concurrent prescriptions of one SMR and one of the specified opioids, within the study period
Exclusion Criteria

Participants aged <18 years; not continuously enrolled in Medicaid during the baseline period; experienced an injury outcome during the baseline or index date; used multiple SMRs concurrently, or were hospitalized on the index date
Methods

Participants were divided into cohorts based on the initiation timing of SMRs and opioids. Injury rates were assessed using Cox proportional hazard models, adjusting for various covariates. Methocarbamol was used as a reference SMR.

Concurrent users of SMRs with hydrocodone, oxycodone, or tramadol were categorized further based on whether the SMR or opioid was initiated first, or both were initiated simultaneously.

The study followed participants from the index date until the injury event, discontinuation of either drug, initiation of different SMR, death, or disenrollment from Medicaid, or the end of data availability on December 31, 2012.
Duration

Retrospective review: from 1999 to 2012

Median follow-up: varied by the cohort and SMR group, ranging from 7 to 29 days
Outcome Measures

Primary outcome: traumatic injury resulting in an emergency department visit or inpatient hospitalization, identified using ICD-9-CM codes
Baseline Characteristics

The baseline characteristics included patient demographics, comorbidities, health care utilization, use of concurrent medications, and specifics about opioid use on the index date and varied among different cohorts.
Results

7,418 injury events were observed during the follow-up, with incidence rates ranging from 89 to 222 per 1,000 person-years across different cohorts.

The adjusted hazard ratios showed varying injury risks: higher injury rates were found for carisoprodol and tizanidine when initiated during existing oxycodone use, and for baclofen and cyclobenzaprine during ongoing tramadol use. Lower injury rates were associated with metaxalone and tizanidine when initiated simultaneously with tramadol.

Three cohorts were associated with statistically significant hazard ratios (HRs):

(i) Among oxycodone users, in the SMR-triggered cohort: adjusted HRs 1.86 (95% confidence interval [CI] 1.23 to 2.82) for carisoprodol and 1.73 (95% CI 1.09 to 2.73) for tizanidine, each vs. methocarbamol

(ii) Among tramadol users, in the synchronically triggered cohort: adjusted HRs 0.69 (95% CI 0.49 to 0.97) for metaxalone and 0.62 (95% CI 0.42 to 0.90) for tizanidine, each vs. methocarbamol

(iii) Among tramadol users, in the SMR-triggered cohort, adjusted HRs 1.51 (95% CI 1.01 to 2.26) for baclofen and 1.48 (95% CI 1.03 to 2.11) for cyclobenzaprine, each vs. methocarbamol
Adverse Events

See results
Study Author Conclusions

In conclusion, the relative injury rate associated with different SMRs used concurrently with the three most dispensed opioids appears to vary depending on the specific opioid and the order of combination initiation. If confirmed by future studies, clinicians should consider the varying injury rates when prescribing SMRs to individuals using hydrocodone, oxycodone, and tramadol.
Critique

Limitations include potential exposure misclassification, lack of adjustment for SMR doses, and possible unmeasured confounding factors owing to the retrospective nature. Further research is needed to confirm findings and elucidate the mechanisms behind observed injury rates of carisoprodol compared to other muscle relaxants.

 

References:

Chen C, Hennessy S, Brensinger CM, et al. Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants. Clin Pharmacol Ther. 2024;116(1):117-127. doi:10.1002/cpt.3248

Background
Background

Carisoprodol is an oral, central-acting, skeletal muscle relaxant used to treat acute musculoskeletal pain, especially acute low back pain, for short durations of up to two or three weeks. Its exact mechanism of action is not fully understood but is thought to involve CNS depression through alterations in neuronal communication within the reticular formation and spinal cord, primarily leading to sedation rather than direct muscle relaxation. Carisoprodol is metabolized to meprobamate, which produces sedative and anxiolytic effects by binding to barbiturate receptor binding sites. The metabolism involves the CYP2C19 enzyme, raising concerns about genetic polymorphisms that may affect drug concentration. Despite these concerns, studies have not associated these genetic variants with an increased risk of mortality from carisoprodol toxicity. [1]

Carisoprodol is available in 250 mg and 350 mg tablets, recommended to be taken three times daily and at bedtime. The drug has an onset of action of about 30 minutes, with effects lasting 4 to 6 hours. Caution is advised for patients with renal or hepatic dysfunction due to the lack of data on proper dosing in these populations. Common side effects include dizziness, drowsiness, and headache. Because of these side effects, particularly the risks associated with CNS depression, carisoprodol is listed on the Beers list, indicating it may be inappropriate for older adults due to the higher risk of side effects outweighing potential benefits. [1]

Comparative studies with other muscle relaxants, such as diazepam and cyclobenzaprine, showed varying results, with some indicating similar effectiveness in pain improvement. The abuse potential of carisoprodol is a significant concern, given its capability to modulate GABAa function and the abuse and dependence risks associated with its active metabolite, meprobamate. Chronic use can lead to withdrawal symptoms upon discontinuation and enhanced CNS depression, particularly in elderly patients and those with renal insufficiency. [1]

The American Pain Society and the American College of Physicians recommend acetaminophen or NSAIDs as first-line treatment for most patients due to their favorable side-effect profile. Following the failure of first-line treatment, skeletal muscle relaxants, benzodiazepines, and opioids may be considered for additional pain relief despite the controversies regarding muscle relaxants' efficacy, adverse effects, and increased cost. Guidelines from Veterans Affairs do not routinely support carisoprodol use, even though they acknowledge it can be helpful short term. Trials that included carisoprodol were associated with an increased risk of sedation and dizziness versus placebo; additionally, the risk of dependence leads to it not being recommended for acute or chronic low back pain by Veterans Affairs. [2], [3]

References:

[1] Witenko C, Moorman-Li R, Motycka C, et al. Considerations for the appropriate use of skeletal muscle relaxants for the management of acute low back pain. P T. 2014;39(6):427-435.
[2] Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society [published correction appears in Ann Intern Med. 2008 Feb 5;148(3):247-8. doi: 10.7326/0003-4819-148-3-200802050-00020]. Ann Intern Med. 2007;147(7):478-491. doi:10.7326/0003-4819-147-7-200710020-00006
static/file/VADoDLBPCPGFinal508
Literature Review
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the safety and efficacy with the use of carisoprodol?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Tables 1-6 for your response.
  Table 1

 

Meta-analyses Assessing Carisoprodol versus other Skeletal Muscle Relaxants in Treating Low Back Pain 

Citation

Design/Intervention

Results

 Conclusions

van Tulder et al., 20031

 

Muscle relaxants vs. placebo

 Meta-analysis; Cochrane review

 

N= 30 randomized and/or double-blinded controlled trials, involving patients diagnosed with non-specific low back pain, treated with muscle relaxants as monotherapy or in combination with other therapeutic modalities

 Main results:
  • Pain relief at 2-4 days (non-benzodiazepine muscle relaxant vs. placebo): RR 0.80 (95% CI 0.71 to 0.89)
  • Global efficacy (muscle relaxant vs. placebo): RR 0.49 (95% CI 0.25 to 0.95)
  • AEs (muscle relaxant vs. placebo): RR 1.5 (95% CI 1.14 to 1.98)

 

Comparative results between skeletal muscle relaxants:

  • Carisoprodol vs cyclobenzaprine-hydrochloride: No statistically significant difference in effectiveness for acute low-back pain (based on 1 small high quality trial)

Authors’ Conclusions:

Muscle relaxants are effective in the management of non‐specific low back pain, but the adverse effects require that they be used with caution. Trials are needed that evaluate if muscle relaxants are more effective than analgesics or non‐steroidal anti‐inflammatory drugs.

 

Critique:

Comparative results between skeletal muscle relaxants:

This meta-analysis identified few directly comparative trials of muscle relaxants, and while the identified trials did not find significant differences in effectiveness, their sample sizes may have been too small to reliably detect significant differences between the drug products. Differences in safety outcomes did not appear to have been assessed.

 

Main results:

Some of the included studies were of lower quality due to aspects such as lack of adequate blinding, failing to evaluate treatment compliance, and inadequate methods of randomization.

Wewege et al., 20232

 

Analgesic medicines vs. placebo, or no treatment

 

  

Systematic review and network meta-analysis

 

N= 98 RCTs (15 ,134 patients) including 69 different medicines or combinations: analgesic medicines

(non-steroidal anti-inflammatory drugs, paracetamol, opioids, anti-convulsant drugs, skeletal muscle relaxants, or corticosteroids) compared with another analgesic medicine, placebo, or no treatment in adults (≥18 years) who reported acute non-specific low back pain (for less than six weeks).

Treatment duration ranged from one day (single administration) to 42 days.		  

Main results:

  • Low confidence data suggested that tolperisone is superior to carisoprodol at reducing pain intensity: mean difference -13.7, (95% CI -24.9 to -2.5).
  • Non-benzodiazepine antispasmodic (mean difference -14.3 [95% CI -18.8 to -9.7], very low confidence), nonselective non-steroidal anti-inflammatory drugs plus non-benzodiazepine antispasmodic (-12.7 [95% CI -17.9 to -7.5], very low confidence), non-selective non-steroidal anti-inflammatory drugs plus antispastic (-13.1 [95% CI -25.5 to -0.7], low confidence) might be associated with the moderate reductions in pain intensity compared with placebo.

 

Comparative results between skeletal muscle relaxants, Mean difference (95% CI):

 

Effectiveness in reducing pain vs placebo:

 

Cyclobenzaprine: -16.7 (-29.4 to -3.9) (Very low confidence);

Carisoprodol: -12.4 (-20.3 to -4.6) (Very low confidence);

Chlorzoxazone: -11.3 (-36 to +13.4) [p= NS] (Very low confidence);

Tizanidine:-6.3 (-13.6 to +0.9) [p= NS] (Very low confidence);

Baclofen + ibuprofen: -5.1 (-17.6 to +7.5) [p= NS] (Very low confidence)

Ibuprofen: -4 (-9.5 to +1.4) [p= NS] (Very low confidence)

 

Safety (95% CI): Any adverse event, RR vs placebo:

  • Data were insufficient for analysis of carisoprodol.
 Authors’ Conclusions:

The comparative effectiveness and safety of analgesic medicines for acute non-specific low back pain are uncertain. Until higher quality randomized controlled trials of head-to-head comparisons are published, clinicians and patients are recommended to take a cautious approach to manage acute non-specific low back pain with analgesic medicines.

 

Critique:

Comparative results between skeletal muscle relaxants: Few directly comparative trials were included in this analysis, and as the dosing regimens assessed were not specified they may not have been equivalent, potentially reducing the reliability of the comparative results between skeletal muscle relaxant agents. Dantrolene did not appear to have been included in search criteria for this analysis, obstructing comparative inferences for dantrolene vs other muscle relaxants based on these results.

The assessed effectiveness data may be inadequate to reliably infer comparative effectiveness, as confidence was very low among all agents’ respective results vs placebo.

The safety of each agent, as assessed by the relative risk of any adverse event, were similar to placebo and may be most reliable, given a moderate level of confidence for the regimens: baclofen + ibuprofen, metaxalone + ibuprofen, and ibuprofen monotherapy.

 

Main results:

Many included studies had concerns regarding bias, and missing ata required imputation for continuous outcomes. 

Abbreviations:

AE= adverse event; CI= Confidence Interval; NS= not statistically significant; RCT= randomized controlled trial; RR= relative risk
References:

[1] van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev. 2003;2003(2):CD004252. doi:10.1002/14651858.CD004252
[2] Wewege MA, Bagg MK, Jones MD, et al. Comparative effectiveness and safety of analgesic medicines for adults with acute non-specific low back pain: systematic review and network meta-analysis. BMJ. 2023;380:e072962. Published 2023 Mar 22. doi:10.1136/bmj-2022-072962
  Table 2

 

Randomized, double-blind trial of carisoprodol 250 mg compared with placebo and carisoprodol 350 mg for the treatment of low back spasm

Design

Randomized, double-blind, placebo-controlled, parallel-group, multicenter trial;

N= 828

Objective

To compare the efficacy and safety of carisoprodol 250 mg and 350 mg tablets taken four times daily with placebo in patients with acute, painful musculoskeletal spasm of the lower back

Study Groups

Carisoprodol 250 mg (n= 271);

Carisoprodol 350 mg (n= 281);

Placebo (n= 276)

Inclusion Criteria

18-65 years old; in general good health; and experiencing moderate to severe back spasm

Exclusion Criteria

Duration of back symptoms >3 days; Sciatic pain or Neurologic signs (numbness, tingling, foot drop) or Abnormal lower-extremity strength, sensation, or reflexes; History of spinal pathology; History of osteoporosis or on systemic steroids; Underlying rheumatologic diseases; Body mass index (BMI) >39 kg/m2

Methods

Patients were randomized to receive carisoprodol 250 mg, carisoprodol 350 mg, or placebo tablets three times daily and at bedtime for up to 7 days. Efficacy evaluations included patient-rated relief from backache and global impression of change.

The Roland-Morris Disability Questionnaire (RMDQ) is a 24-item, self-reported disability scale that measures daily function in completing activities affected by back pain.

Duration

1 week

Outcome Measures

Primary: Patient-rated relief from starting backache and global impression of change on treatment day 3

Secondary: RMDQ; patient-rated medication helpfulness; time to symptom improvement; and physician-assessed range of motion

Baseline Characteristics

  

Carisoprodol 250 mg

(n= 264)

Carisoprodol 350 mg

(n= 273)

Placebo

(n= 269)

  

Age, years

 40.9 ± 11.7 40.5 ± 12.4 40.7 ± 13.1  

Female

52.3% 55.7% 60.6%  

Caucasian

 72.3% 76.2% 69.6%  

Non-Hispanic

 69.7% 75.5% 75.8%  

Onset of lower-back pain, days

 1.60 ± 0.75 1.65 ± 0.7 1.62 ± 0.73  

Lower-back pain severity

Moderate

Severe

 

65.5%

34.5%

 

65.9%

34.1%

 

62.8%

37.2%

  

RMDQ score

 11.5 ± 5.3 11.8 ± 5.3 11.2 ± 5.6  

Range of motion, cm

 6.6 ± 3.3 6.4 ± 3 6.6 ± 3.2  

Carisoprodol daily dose, mean (range)

 867.4 mg (0 to 1000 mg) 1196.0 mg (350 to 1400 mg) N/A  

Took study drug for 4-7 days

 69.7% 66.3% 64.5%  

Results

Endpoint

Carisoprodol 250 mg

(n= 264)

Carisoprodol 350 mg

(n= 273)

  

Placebo

(n= 269)

p-Value

 RMDQ score, Mean difference vs placebo (95% Confidence Interval) 

Day 3

Day 7

 

1 (0.29 to 1.72)

1.1 (0.25 to 1.91)

 

1 (0.27 to 1.68)

1.3 (0.50 to 2.14)

 

N/A

N/A

 

N/A

N/A
Time to moderate or marked symptom improvement based on global impression of change, median days 4  4  5  <0.003 

Treatment-emergent adverse events

Drowsiness

Dizziness

Headache

Nausea

 

12.2%

5.9%

5.9%

1.5%

 

16.1%

6.8%

3.2%

4.3%

 

6.5%

0.7%

2.5%

2.5%

 N/A

Study Discontinuations

9.6% (n= 26)

15% (n= 42)

17.4% (n= 48)

 N/A

Serious Adverse Events

0

0

0

 N/A

Primary outcomes: Carisoprodol 250 mg was significantly more effective than placebo for both primary endpoints (p< 0.005). No significant difference was found between the 250 mg and 350 mg doses.

Secondary outcomes not listed above: Treatment with carisoprodol 250- or 350-mg tablets did not significantly increase physician-assessed range of motion on day 3 or 7. Patient-rated medication helpfulness was significantly (p< 0.0001) higher for both doses compared to placebo on day 3 and day 7.

Study Author Conclusions

In conclusion, carisoprodol 250 mg three times daily and at bedtime is effective and well-tolerated for patients with painful, acute musculoskeletal spasm. Patients returned to better functional status, based on the RMDQ, faster with both dosages of carisoprodol than with placebo. The efficacy of carisoprodol 250 mg was comparable to carisoprodol 350 mg with better tolerability, including less drowsiness and fewer discontinuations due to adverse events. The efficacy of carisoprodol was not dependent on a sedative effect; patients improved whether or not they reported sedation.

InpharmD Researcher Critique

The short study duration (1 week) and the lack of an active comparator limit the potential clinical inferences that can be drawn from these results. 



References:

Serfer GT, Wheeler WJ, Sacks HJ. Randomized, double-blind trial of carisoprodol 250 mg compared with placebo and carisoprodol 350 mg for the treatment of low back spasm. Curr Med Res Opin. 2010;26(1):91-99. doi:10.1185/03007990903382428
  Table 3

 

Double-blind, Placebo Controlled Trial of Carisoprodol 250-mg Tablets in the Treatment of Acute Lower-back Spasm

Design

Prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter (49 sites in the United States) trial;

N= 561

Objective

The objective of this placebo-controlled trial was to determine the efficacy and safety of carisoprodol (Soma, MedPointe Pharmaceuticals, Somerset, NJ, USA), a centrally acting skeletal muscle relaxant used to treat acute, painful musculoskeletal conditions, at a dosage of 250 mg three times daily and at bedtime in patients with acute, painful muscle spasm of the lower back.

Study Groups

Carisoprodol 250 mg (n= 277)

Placebo (n= 285)

Inclusion Criteria

 Patients 18-65 years-old; moderate-to-severe lower back muscle spasm and backache; generally good health

Exclusion Criteria

Back symptom duration >3 days; sciatic pain or any neurologic signs or abnormal lower-extremity strength, reflexes or sensory function; positive straight leg raise test; history of spinal pathology; osteoporosis; rheumatologic diseases; BMI >39 kg/m²

Methods

Patients were randomly assigned to receive either carisoprodol 250 mg or a placebo. They recorded their ratings of back pain and global impression of change in diaries. Secondary measures included the Roland-Morris Disability Questionnaire (RMDQ), time to symptom improvement, patient-rated medication helpfulness, and physician assessment of range of motion. Doses were taken three times daily and at bedtime.

Patient-rated relief from starting backache: Patients used diary cards to record the degree of relief with study medication at 12-h intervals (Complete relief= 4, a lot of relief= 3, some relief= 2, a little relief= 1, no relief= 0)

Patient-rated global impression of change: Patient was asked: 'Compared with how you felt before starting study medication, and regardless of whether you think the change was due to medicine, please indicate if you have experienced; completed at 12-h intervals (Marked improvement= 4, moderate improvement= 3, mild improvement= 2, no change= 1, worsening= 0)

Patient-rated medication helpfulness: Patients were asked at baseline, Day 3, Day 7: 'How would you rate this study medication in improving your condition?" (Excellent= 4, very good= 3, good= 2, fair= 1, poor= 0)

Time to symptom improvement: First time there was an assessment of 3 (moderate improvement) or 4 (marked improvement) in the patient's rating of global impression of change

Duration

Intervention: 7 days

Study period: August 11, 2005 through June 8, 2006

Outcome Measures

Primary outcomes: patient-rated global impression of change at day 3 and patient-rated relief from starting backache at day 3

Secondary outcomes: RMDQ scores; patient-rated medication helpfulness; time to symptom improvement; and range of motion

Baseline Characteristics

  

Carisoprodol, 250 mg

(n= 269)

Placebo

(n=278)

  

Age, years

 39.3 ± 11.82 41.5 ± 11.7  

Female

48.7% 55%  

Caucasian

 74% 77.3%  

Non-Hispanic

 63.6% 65.1%  

Onset of lower-back symptoms, days

 1.68 ± 0.78 1.73 ± 0.79  

Lower back pain severity:

Moderate

Severe

 

74.3%

25.3%

 

73.7%

25.9%

  

RMDQ score

10.4 ± 4.9

10.3 ± 5.0

  

Range of motion, cm

6.3 ± 3

5.9 ± 2.8

  

 

Results

Endpoint

Carisoprodol 250 mg

(n= 277)

Placebo

(n= 285)

p-Value

Global impression of change: Moderate or marked improvement at:

Day 2

Day 3

Day 7

 

(Undisclosed)

39%

(Undisclosed)

 

(Undisclosed)

19%

(Undisclosed)

 

p< 0.0001

p< 0.0001

p< 0.0001

Patient-rated relief from starting backache: Moderate or marked improvement at:

Day 2

Day 3

Day 7

 

(Undisclosed)

41%

(Undisclosed)

 

(Undisclosed)

21%

(Undisclosed)

 

p< 0.0001

p< 0.0001

p< 0.0001

Patient-rated medication helpfulness: good or excellent at:

Day 3

Day 7

 

23%

(Undisclosed)

 

11%

(Undisclosed)

 

<0.0001

<0.0001

RMDQ score

Day 3

Day 7

 

6.9

4.1

 

8.7

6.2

 

<0.0001

<0.0001

Moderate to marked symptom improvement

73.2%

53.6%

<0.0001

Time to symptom improvement, median days

3

6

<0.0001

Range of motion, cm at:

Day 3

Day 7

 

7.25

8.2

 

6.69

7.68

 

0.119

0.074

Treatment-emergent adverse events* occurring in ≥ 3% of patients in either treatment group

Drowsiness/Sedation

Dizziness

Headache

 

13.4%

9.7%

3.6%

 

4.6%

3.2%

1.4%

 N/A

Serious adverse events

0

0

 N/A

Study discontinuations

11.2%

13.2%

 N/A

Study Author Conclusions

In this study, patients with acute muscle spasm of the lower back had significantly greater and more rapid relief from starting backache, and had improved functional status, as measured by the RMDQ, during treatment with carisoprodol 250-mg tablets compared to placebo.

InpharmD Researcher Critique

The short study duration (1 week) and the lack of an active comparator limit the potential clinical inferences that can be drawn from these results. 



References:

Ralph L, Look M, Wheeler W, Sacks H. Double-blind, placebo-controlled trial of carisoprodol 250-mg tablets in the treatment of acute lower-back spasm. Curr Med Res Opin. 2008;24(2):551-558. doi:10.1185/030079908x261014
  Table 4

 

Risk of Injury Associated with Skeletal Muscle Relaxant Use in Older Adults

Design

Observational population-based retrospective analysis;

N= 132,277 (All cases and controls who were taking skeletal muscle relaxants: N= 1,166)

Objective

The study aimed to investigate the relationship between the use of skeletal muscle relaxants and the subsequent risk of injury in older adults.

Study Groups

Cases (those with documented injuries) (n= 27,974)

Controls (those without injuries) (n= 104,303)

Inclusion Criteria

Participants enrolled in the health system, aged 65 or older (and cases were alive on the index date of injury); health record data from January 2009 through December 2010

Exclusion Criteria

Resided in long-term care facilities or nursing homes before the index date

Methods

Cases and controls were selected from a base population of older adults, which were then analyzed to segregate data for cases and controls who also were taking skeletal muscle relaxants. Skeletal muscle relaxant exposure was assessed for within 60 days prior to the injury date using prescription records. Conditional logistic regression was used to adjust for various covariates, and risk estimates were presented as odds ratios.

The resulting adjusted odds ratios were adjusted based on age, sex, previous injury, Diagnostic Cost Groups comorbidity score, medications, and concomitant diseases.

Duration

Health record data interval assessed: January 2009 through December 2010

Outcome Measures

Primary outcome: the incidence of injury resulting in hospitalization or emergency/urgent care visits among older adults using skeletal muscle relaxants compared to non-users

Baseline Characteristics

  

Cases

(n= 27,974)

Controls

(n= 104,303)

  

Age, years

 75.5 ±7.5 75.4 ±7.4  

Women

 61.3% 61.5%  

DxCG score

 1.14 ±1.33 0.80 ±1.01  

Skeletal muscle relaxant

Carisoprodol

Cyclobenzaprine

Methocarbamol

 

7.4% (n= 27)

53.2% (n= 194)

38.9% (n= 142)

 

4.9% (n= 39)

57.2% (n= 458)

37.5% (n= 300)

  

Other medications

Antihypertensives

Antidepressants

Opioids

 

52.2%

26.9%

35.3%

 

48.5%

17.5%

26.3%

  

Results

Endpoint

All cases and controls who were taking skeletal muscle relaxants

N= 1,166

p-Value
 

Risk of injury with use of skeletal muscle relaxants vs no use, unadjusted odds ratio (OR) [95% confidence interval (CI)]:

All skeletal muscle relaxants

Carisoprodol

Cyclobenzaprine

Methocarbamol

 

1.73 [1.52 to 1.96]

2.53 [1.54 to 4.15]

1.6 [1.35 to 1.9]

1.79 [1.46 to 2.2]

  

<0.001

0.036

0.029

0.001

Risk of injury with use of skeletal muscle relaxants vs no use, adjusted OR [95% CI]:

All skeletal muscle relaxants

Carisoprodol

Cyclobenzaprine

Methocarbamol

  

1.32 [1.16 to 1.5]

1.73 [1.04 to 2.88]

1.22 [1.02 to 1.45]

1.42 [1.16 to 1.75]

 

<0.001

0.036

0.029

0.001

Study Author Conclusions

In this study, the use of skeletal muscle relaxants was associated with an increased risk of injury among older adults. Through multiple risk factor reduction interventions, falls and injuries can be prevented in community-dwelling older adults. One of the critical strategies for preventing these potentially fatal events includes stopping the use of high-risk medications such as skeletal muscle relaxants.

InpharmD Researcher Critique

All analyzed skeletal muscle relaxants were found to significantly increase the risk of injury in the observed patient population. However, as the carisoprodol results were derived from only 27 cases (compared to 194 cyclobenzaprine cases and 142 methocarbamol cases) and the confidence interval for risk of injury with carisoprodol nearly crossed 1 in the adjusted OR analysis, which would represent a non-statistically significant difference versus no skeletal muscle relaxant use, it is possible that these results may not reliably represent carisoprodol in this population.



References:

Spence MM, Shin PJ, Lee EA, Gibbs NE. Risk of injury associated with skeletal muscle relaxant use in older adults. Ann Pharmacother. 2013;47(7-8):993-998. doi:10.1345/aph.1R735
  Table 5

 

Subjective and Psychomotor Effects of Carisoprodol in Combination With Oxycodone in Healthy Volunteers

Design

Prospective, double-blind, randomized, placebo-controlled, triple-dummy, crossover trial;

N= 15

Objective

The study aimed to investigate the combined effects of carisoprodol and oxycodone on subjective measures of abuse liability and psychomotor performance in healthy volunteers.

Study Groups

Healthy volunteers (N= 15)

Inclusion Criteria

Healthy volunteers; 21-39 years-old; have a high school diploma or equivalent; speak English fluently; and consume alcohol at some level

Exclusion Criteria

Total drug abstention; history of psychiatric or substance use disorders; and any significant medical conditions

Methods

All subjects were treated at different cross-over intervals with: placebo vs carisoprodol 350 mg vs oxycodone 10 mg vs carisoprodol 350 mg followed at 60 minutes by oxycodone 10 mg.

Subjective effects were measured using various questionnaires and scales, while psychomotor performance was evaluated using the Digit Symbol Substitution Test, logical reasoning test, auditory reaction time test, eye-hand coordination test, and a memory recall test.

Duration

Intervention: The study sessions were conducted over a period from 0800 to 1545 hours, with each session being at least one week apart.

Outcome Measures

Primary outcomes: subjective measures (like feelings of euphoria and drug liking) and psychomotor performance

Secondary outcomes: physiological parameters (ex: pupil size)

Baseline Characteristics

 The 15 participants (8 males and 7 females) had a mean age of 27 years. All consumed alcohol (mean 2.8 drinks per week), 3 smoked tobacco, and 5 used marijuana.

Results

The combination of carisoprodol and oxycodone generated significantly greater subjective and psychomotor impairment effects compared to either drug alone. Specific subjective effects included increased feelings of euphoria and drug liking, while psychomotor performance declined as measured by reaction time and logical reasoning tests.

Study Author Conclusions

This is the first study that we are aware of that has shown that carisoprodol and oxycodone, two drugs that are sometimes co-prescribed for relief of pain, produce effects when administered “together” (i.e., separated by 60 min) that are of greater magnitude than when they are administered alone. Some of the effects were not benign, and are of concern from both abuse liability and public safety standpoints.

InpharmD Researcher Critique

Clinical inferences that can be derived from these results are limited by the use of a healthy volunteer population and the short duration of the interventions (1 administration session for each intervention cross-over).



References:

Zacny JP, Paice JA, Coalson DW. Subjective and psychomotor effects of carisoprodol in combination with oxycodone in healthy volunteers. Drug Alcohol Depend. 2012;120(1-3):229-232. doi:10.1016/j.drugalcdep.2011.07.006

  Table 6

Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants
Design

Retrospective, database review

N= 9 cohorts
Objective

To compare the injury rates associated with different skeletal muscle relaxants (SMRs) when used concurrently with the three most commonly dispensed opioids—hydrocodone, oxycodone, and tramadol—and to determine if the risk varies by specific SMR and order of initiation
Inclusion Criteria

Adult Medicaid beneficiaries from California, Florida, New York, and Pennsylvania, with concurrent prescriptions of one SMR and one of the specified opioids, within the study period
Exclusion Criteria

Participants aged <18 years; not continuously enrolled in Medicaid during the baseline period; experienced an injury outcome during the baseline or index date; used multiple SMRs concurrently, or were hospitalized on the index date
Methods

Participants were divided into cohorts based on the initiation timing of SMRs and opioids. Injury rates were assessed using Cox proportional hazard models, adjusting for various covariates. Methocarbamol was used as a reference SMR.

Concurrent users of SMRs with hydrocodone, oxycodone, or tramadol were categorized further based on whether the SMR or opioid was initiated first, or both were initiated simultaneously.

The study followed participants from the index date until the injury event, discontinuation of either drug, initiation of different SMR, death, or disenrollment from Medicaid, or the end of data availability on December 31, 2012.
Duration

Retrospective review: from 1999 to 2012

Median follow-up: varied by the cohort and SMR group, ranging from 7 to 29 days
Outcome Measures

Primary outcome: traumatic injury resulting in an emergency department visit or inpatient hospitalization, identified using ICD-9-CM codes
Baseline Characteristics

The baseline characteristics included patient demographics, comorbidities, health care utilization, use of concurrent medications, and specifics about opioid use on the index date and varied among different cohorts.
Results

7,418 injury events were observed during the follow-up, with incidence rates ranging from 89 to 222 per 1,000 person-years across different cohorts.

The adjusted hazard ratios showed varying injury risks: higher injury rates were found for carisoprodol and tizanidine when initiated during existing oxycodone use, and for baclofen and cyclobenzaprine during ongoing tramadol use. Lower injury rates were associated with metaxalone and tizanidine when initiated simultaneously with tramadol.

Three cohorts were associated with statistically significant hazard ratios (HRs):

(i) Among oxycodone users, in the SMR-triggered cohort: adjusted HRs 1.86 (95% confidence interval [CI] 1.23 to 2.82) for carisoprodol and 1.73 (95% CI 1.09 to 2.73) for tizanidine, each vs. methocarbamol

(ii) Among tramadol users, in the synchronically triggered cohort: adjusted HRs 0.69 (95% CI 0.49 to 0.97) for metaxalone and 0.62 (95% CI 0.42 to 0.90) for tizanidine, each vs. methocarbamol

(iii) Among tramadol users, in the SMR-triggered cohort, adjusted HRs 1.51 (95% CI 1.01 to 2.26) for baclofen and 1.48 (95% CI 1.03 to 2.11) for cyclobenzaprine, each vs. methocarbamol
Adverse Events

See results
Study Author Conclusions

In conclusion, the relative injury rate associated with different SMRs used concurrently with the three most dispensed opioids appears to vary depending on the specific opioid and the order of combination initiation. If confirmed by future studies, clinicians should consider the varying injury rates when prescribing SMRs to individuals using hydrocodone, oxycodone, and tramadol.
Critique

Limitations include potential exposure misclassification, lack of adjustment for SMR doses, and possible unmeasured confounding factors owing to the retrospective nature. Further research is needed to confirm findings and elucidate the mechanisms behind observed injury rates of carisoprodol compared to other muscle relaxants.

 

References:

Chen C, Hennessy S, Brensinger CM, et al. Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants. Clin Pharmacol Ther. 2024;116(1):117-127. doi:10.1002/cpt.3248