A Clinical Analysis of Combining Skeletal Muscle Relaxants and Anti-Inflammatory Agents

Executive Summary: A Nuanced Answer to a Complex Question

The question of whether one can safely and effectively take a skeletal muscle relaxant with an anti-inflammatory drug is a common one, particularly for individuals experiencing acute musculoskeletal pain.

While the combination is frequently prescribed in clinical practice for short-term pain management ¹, a definitive “yes” or “no” answer is both medically inaccurate and potentially unsafe.

The decision to co-administer these medications is highly individualized and hinges on a careful evaluation of potential benefits versus significant risks.

The clinical rationale for this combination therapy is to provide a synergistic, or “one-two punch,” effect: the anti-inflammatory drug targets the underlying inflammation, while the muscle relaxant addresses the associated painful muscle spasms.²

However, the evidence supporting superior pain relief from this combination is mixed and, in many well-controlled studies, inconclusive.⁴

Some research indicates that adding a muscle relaxant to a nonsteroidal anti-inflammatory drug (NSAID) does not significantly improve pain outcomes but does increase the incidence of side effects, particularly those affecting the central nervous system.⁶

The primary risks associated with this combination can be broadly categorized into two areas.

First is the potential for additive central nervous system (CNS) depression, leading to enhanced drowsiness, dizziness, and impaired coordination, which can increase the risk of falls and accidents.²

Second are the well-documented risks inherent to NSAIDs, including gastrointestinal irritation and bleeding, potential kidney (renal) damage, and an increased risk of adverse cardiovascular events.⁸

Ultimately, the safety and appropriateness of this combination therapy depend on three critical variables: the specific muscle relaxant and anti-inflammatory drugs being used, the patient’s individual health profile, including age and pre-existing medical conditions, and the duration of treatment, which should be strictly limited to short-term use.

This report serves as a comprehensive educational resource to facilitate an informed discussion with a healthcare provider.

Any decision to combine these medications must be made under the guidance of a qualified medical professional who can conduct a personalized risk-benefit assessment.

Understanding the Components: A Primer on Muscle Relaxers and NSAIDs

To comprehend the complexities of combining these medications, it is essential to first understand that “muscle relaxer” and “anti-inflammatory” are broad categories, each encompassing drugs with distinct mechanisms of action and risk profiles.

The safety of their combination is determined not by their general class, but by the specific pharmacology of the individual agents involved.

The Role of Skeletal Muscle Relaxants (SMRs)

Skeletal muscle relaxants (SMRs) are a heterogeneous group of drugs primarily used to treat muscle spasms and spasticity.

Contrary to what their name might suggest, most SMRs do not act directly on the skeletal muscle fibers.

Instead, they exert their effects by depressing the central nervous system (CNS), which leads to sedation and a reduction in the brain’s perception of muscle pain and tension.¹¹

They are broadly divided into two main classes.¹³

• Antispasmodics: This class of SMRs acts on the CNS, often at the level of the brainstem or spinal cord, to reduce acute muscle spasms caused by musculoskeletal injuries like strains or sprains. They are typically prescribed for short-term use. Examples include cyclobenzaprine, carisoprodol, and methocarbamol.
• Antispastics: This class of SMRs is used to treat spasticity—a condition of muscle tightness and stiffness—that arises from chronic neurological disorders such as multiple sclerosis (MS), cerebral palsy, or spinal cord injuries. They may act on the spinal cord or directly on the skeletal muscle itself. Examples include baclofen and dantrolene. Tizanidine is a unique agent that exhibits both antispastic and antispasmodic properties.¹³

The distinction between these classes is not merely academic; it dictates their appropriate use and potential side effects.

An antispasmodic for an acute back strain works differently and carries different risks than an antispastic used for managing Ms.

The Role of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs are a cornerstone of pain and inflammation management.

They are available both over-the-counter (OTC) and by prescription.

Their primary mechanism of action is the inhibition of cyclooxygenase (COX) enzymes.⁸

These enzymes are responsible for producing chemical messengers called prostaglandins, which play a key role in mediating inflammation, pain, and fever.

There are two primary COX isoenzymes, and the distinction between them is critical to understanding the benefits and risks of NSAIDs.⁸

• COX-1: This enzyme is “constitutively” active, meaning it is always present in the body. It performs essential housekeeping functions, such as producing prostaglandins that protect the stomach lining from its own acid and maintaining blood flow to the kidneys.
• COX-2: This enzyme is “inducible,” meaning its production is ramped up at sites of injury and inflammation. It is the primary target for reducing inflammatory pain.

NSAIDs are classified based on their selectivity for these enzymes:

• Non-selective NSAIDs: These drugs, such as ibuprofen (Advil, Motrin) and naproxen (Aleve), inhibit both COX-1 and COX-2. While effective at reducing inflammation (by blocking COX-2), their inhibition of COX-1 can lead to common side effects like stomach irritation and an increased risk of gastrointestinal ulcers and bleeding.⁸
• COX-2 Selective NSAIDs: These drugs, such as celecoxib (Celebrex), were developed to primarily target the COX-2 enzyme, theoretically providing anti-inflammatory benefits with a lower risk of gastrointestinal side effects. However, they have been associated with their own set of risks, particularly concerning cardiovascular health.⁸

This fundamental difference in mechanism means that the choice of NSAID significantly influences the risk profile of any combination therapy.

Table 1: Common Skeletal Muscle Relaxants (Prescription & OTC)

Drug Name (Generic)	Common Brand Name(s)	Class	Typical Use
Carisoprodol	Soma, Vanadom	Antispasmodic (Nonbenzodiazepine)	Acute, painful musculoskeletal conditions (short-term)
Chlorzoxazone	Parafon Forte DSC, Lorzone	Antispasmodic	Acute, painful musculoskeletal conditions
Cyclobenzaprine	Flexeril, Amrix, Fexmid	Antispasmodic (Nonbenzodiazepine)	Muscle spasms from acute musculoskeletal conditions
Metaxalone	Skelaxin	Antispasmodic (Nonbenzodiazepine)	Acute, painful musculoskeletal conditions
Methocarbamol	Robaxin	Antispasmodic (Nonbenzodiazepine)	Acute, painful musculoskeletal conditions (available OTC)
Orphenadrine	Norflex	Antispasmodic	Muscle spasms, pain
Diazepam	Valium	Antispasmodic (Benzodiazepine)	Severe muscle spasms, spasticity
Baclofen	Lioresal	Antispastic	Spasticity from MS, spinal cord injury
Dantrolene	Dantrium	Antispastic	Spasticity, malignant hyperthermia
Tizanidine	Zanaflex	Antispastic & Antispasmodic	Spasticity from MS, spinal cord injury

Data sourced from ¹³, and.¹³

Table 2: Common Nonsteroidal Anti-Inflammatory Drugs (Prescription & OTC)

Drug Name (Generic)	Common Brand Name(s)	Class / Type	Availability
Ibuprofen	Advil, Motrin	Propionic Acid (Non-selective)	OTC / Prescription
Naproxen	Aleve, Naprosyn	Propionic Acid (Non-selective)	OTC / Prescription
Aspirin	Bayer, Ecotrin	Acetylated Salicylate (Non-selective)	OTC
Diclofenac	Voltaren, Cataflam	Acetic Acid (Non-selective)	Prescription / Topical OTC
Meloxicam	Mobic	Enolic Acid (Preferentially COX-2)	Prescription
Indomethacin	Indocin	Acetic Acid (Non-selective)	Prescription
Ketorolac	Toradol	Acetic Acid (Non-selective)	Prescription (short-term)
Celecoxib	Celebrex	COX-2 Selective	Prescription

Data sourced from ⁸, and.⁸

The Rationale and Evidence for Combination Therapy

The clinical logic for prescribing a muscle relaxant and an NSAID together is straightforward and intuitive.

Many acute musculoskeletal injuries, such as a lower back strain, present with two distinct but related problems: inflammation from the tissue damage and a reflexive, painful tightening of the surrounding muscles, known as a spasm.¹

The theory is that by using two drugs with different mechanisms, clinicians can address both components of the pain simultaneously.

The NSAID works to reduce the underlying inflammation, while the SMR aims to break the cycle of muscle spasm and pain.²

This “one-two punch” approach is intended to provide more comprehensive and faster relief than either medication could achieve on its own.

A Critical Review of Clinical Efficacy

Despite the compelling rationale, the clinical evidence supporting the superior efficacy of combination therapy is surprisingly inconsistent and far from conclusive.

The medical literature presents a conflicting picture, where clinical habit and some studies suggest a benefit, while other, more rigorous trials and regulatory statements cast doubt.

Some sources and clinical perspectives support the combination, especially for short-term relief of conditions like acute low back and neck pain.

The argument is that for patients with both inflammation and significant spasms, the dual-action approach can lead to more complete symptom relief and improved mobility.²

One study, for instance, found that a combination of the muscle relaxant chlorzoxazone and ibuprofen demonstrated superior efficacy compared to ibuprofen monotherapy for pain relief.²

However, a substantial body of evidence challenges this conclusion.

Multiple studies have found that adding a muscle relaxant to an NSAID provides little to no additional analgesic benefit.

For example, a study of emergency department patients with acute myofascial strain found that adding cyclobenzaprine to ibuprofen did not improve pain relief and, on the contrary, was associated with a higher rate of CNS side effects.⁴

This finding is echoed in other analyses, which conclude that the combination is not proven to be more effective than either drug taken alone.⁶

This lack of proven synergy is formally acknowledged in regulatory documents.

The FDA-approved labeling for cyclobenzaprine (Flexeril), one of the most commonly prescribed muscle relaxants, explicitly states, “No well-controlled studies have been performed to indicate that FLEXERIL enhances the clinical effect of aspirin or other analgesics”.⁷

Furthermore, major clinical practice guidelines, such as those from the American College of Physicians (ACP), recommend NSAIDs

or SMRs as alternative first-line pharmacologic options for acute low back pain, which implies they are viewed as separate choices rather than a required pair.¹⁵

This discrepancy between common clinical practice and the findings of controlled trials may arise from several factors.

It is possible that the sedative effects of the muscle relaxant are perceived by some patients as “relief,” even if objective pain scores do not significantly change; the patient simply feels drowsy and is less aware of the discomfort.

Alternatively, the combination may indeed be beneficial for a very specific subset of patients—perhaps those with exceptionally severe and persistent spasms—whose positive results are diluted when averaged into larger, more heterogeneous study populations.

However, for the average patient, the available evidence suggests that adding a muscle relaxant to an NSAID is more likely to introduce additional side effects than it is to provide a clinically significant improvement in pain relief.⁴

This suggests that the decision to combine these agents should be a deliberate one, reserved for specific clinical situations rather than being a default strategy.

A Comprehensive Analysis of Potential Risks and Side Effects

While the benefits of combination therapy are debated, the risks are well-documented and multifactorial.

The “interaction” between a muscle relaxant and an NSAID is less about a direct chemical reaction and more about the compounding of risks to multiple organ systems.

A patient taking both is simultaneously exposing their body to potential stressors from two distinct pharmacological sources, creating a cumulative burden that must be carefully considered.

The Primary Concern: Additive Central Nervous System (CNS) Depression

The most immediate and predictable adverse effect of combining these drugs is the potentiation of CNS depression.

SMRs are, by design, CNS depressants.¹¹

When taken with an NSAID, which can also cause dizziness and drowsiness in some individuals, these effects become additive.

Patients may experience ²:

• Enhanced drowsiness, sedation, and fatigue
• Dizziness and lightheadedness
• Confusion and difficulty concentrating
• Impaired coordination and motor control

These symptoms are not merely inconvenient; they pose significant safety risks.

They can lead to an increased risk of falls, particularly in older adults, and can impair a person’s ability to drive a vehicle or operate heavy machinery safely.⁴

This risk is dramatically amplified when combined with other CNS depressants.

It is critical to avoid consuming alcohol while taking this combination.

Similarly, caution is required when co-administering with other CNS-active medications like opioids, benzodiazepines (e.g., Xanax, Ativan), certain antidepressants, and sleep aids, as this can lead to profound sedation, respiratory depression, and other life-threatening complications.³

Gastrointestinal (GI) Complications

The risk to the gastrointestinal system is driven almost entirely by the NSAID component of the therapy.

By inhibiting the protective COX-1 enzyme, NSAIDs reduce the natural defenses of the stomach lining, making it vulnerable to acid.⁸

This can lead to a range of complications, from mild stomach irritation to more severe issues such as ²:

• Gastritis (inflammation of the stomach lining)
• Peptic ulcers
• Gastrointestinal bleeding
• In rare cases, perforation of the stomach or intestine

The risk of these complications increases with higher doses, longer duration of use, and in individuals with a history of ulcers or GI bleeding.⁶

While taking NSAIDs with food may lessen immediate stomach upset, it does not eliminate the underlying risk of developing ulcers or bleeding.²³

Impact on Vital Organs

The combined use of SMRs and NSAIDs places a burden on the body’s primary metabolic and excretory organs: the liver and kidneys.

A pre-treatment assessment by a physician is crucial not just to check for a single contraindication, but to evaluate the patient’s total organ system capacity to handle the combined pharmacological load.

• Kidney (Renal) Function: NSAIDs pose a significant risk to the kidneys. They can constrict blood vessels that supply the kidneys, reducing blood flow and impairing function. Over time, or with high doses, this can lead to acute kidney injury or the worsening of pre-existing chronic kidney disease.⁶ This risk is higher in older adults and those with underlying heart disease or dehydration. Certain SMRs, such as metaxalone and injectable methocarbamol, are also specifically contraindicated in patients with severe renal impairment, adding another layer of risk.¹⁰
• Liver (Hepatic) Function: While high-dose or long-term NSAID use can strain the liver, the more acute risk in this combination often comes from the SMR. Several muscle relaxants are associated with hepatotoxicity (liver damage), ranging from mild, reversible elevations in liver enzymes to severe, and in the case of dantrolene, potentially fatal liver injury.²⁴ Specific SMRs with notable liver warnings include
  chlorzoxazone, tizanidine, and dantrolene.²⁴ Other SMRs, like cyclobenzaprine and metaxalone, are metabolized by the liver and must be used with caution and often at lower doses in patients with hepatic impairment, as their effects will be prolonged and intensified.⁷
• Cardiovascular Health: Both drug classes carry potential cardiovascular risks. Long-term use of most NSAIDs (with the possible exception of low-dose aspirin) is associated with an increased risk of high blood pressure, heart attack, and stroke.⁸ The NSAID diclofenac appears to carry one of the highest risks.⁸ On the SMR side, cyclobenzaprine is structurally similar to tricyclic antidepressants and is contraindicated in patients with certain heart conditions, including arrhythmias, heart block, congestive heart failure, and in those who have recently had a heart attack.²⁴

Drug-Specific Interaction Profiles: A Case-by-Case Examination

The general risks of combination therapy must be refined by examining the specific drugs being paired, as the interaction profiles are not uniform across the classes.

While drug interaction databases provide valuable guidance, it is important to heed their common caveat: the absence of a documented interaction does not definitively mean that no interaction exists.²⁷

Consultation with a healthcare provider or pharmacist is essential.

Cyclobenzaprine (Flexeril) with Ibuprofen or Naproxen

This is one of the most frequently prescribed combinations.

Interaction checkers generally find no direct pharmacological interaction between cyclobenzaprine and common NSAIDs like ibuprofen or naproxen.³

The primary concern is the

additive nature of their side effects.

The combination is well-known to increase drowsiness, dizziness, and dry mouth more than either agent alone.⁶

As noted previously, some studies have specifically linked this combination to a greater prevalence of CNS side effects without a corresponding improvement in pain relief.⁴

This pairing is generally considered safe only for short-term use (2-3 weeks) in healthy individuals.³

Methocarbamol (Robaxin) with Ibuprofen (Advil)

This combination appears to have one of the most favorable interaction profiles.

Multiple sources, including bioavailability studies, indicate that there is no known pharmacological interaction between methocarbamol and ibuprofen; they do not interfere with each other’s absorption or metabolism.²⁹

However, this does not eliminate the risk of overlapping side effects.

A patient taking both may still experience increased drowsiness, dizziness, or constipation.³⁰

Furthermore, because both drugs are metabolized by the liver, caution is still warranted in patients with hepatic impairment.³⁰

Carisoprodol (Soma) with Naproxen

While interaction checkers report no direct pharmacological interaction between carisoprodol and naproxen ¹⁹, this combination carries a unique and significant risk.

Carisoprodol is metabolized in the body to meprobamate, a substance with sedative and anti-anxiety properties that has a high potential for abuse and physical dependence.¹²

For this reason, carisoprodol is classified as a controlled substance in many jurisdictions.

Its use, especially for more than 2-3 weeks, can lead to tolerance, withdrawal symptoms upon cessation, and addiction.²⁴

This inherent abuse potential makes the carisoprodol/NSAID combination a higher-risk choice compared to other pairings.

Baclofen with Diclofenac (or other NSAIDs)

The primary concern when combining baclofen with an NSAID like diclofenac is the potential for therapeutic duplication.

If a patient were to take a product containing an NSAID (e.g., a topical gel with flurbiprofen) and also take an oral NSAID like diclofenac, they would be taking two drugs from the same class.

This is generally not recommended as it significantly multiplies the risk of NSAID-related side effects, especially severe gastrointestinal complications like bleeding and perforation.²³

When combining baclofen with a single NSAID, the standard risk profile applies: additive CNS depression from baclofen and the GI, renal, and cardiovascular risks from the NSAID.

Table 3: Summary of Key Drug-Drug Interactions and Associated Risks

SMR Drug	NSAID Drug	Known Pharmacological Interaction?	Primary Combined Risk(s)	Key Considerations
Cyclobenzaprine	Ibuprofen, Naproxen	No direct interaction found.27	Additive CNS depression (drowsiness, dizziness), dry mouth.6	Efficacy for superior pain relief is unproven.4 Use with caution in patients with liver or heart conditions.7
Methocarbamol	Ibuprofen	No known interaction.29	Additive drowsiness, dizziness. Both metabolized by the liver.30	Considered a pharmacologically “cleaner” combination, but general risks of CNS depression and NSAID side effects remain.
Carisoprodol	Naproxen	No direct interaction found.19	Additive CNS depression. High risk of abuse, dependence, and withdrawal associated with carisoprodol.24	Risk of dependence makes this a less desirable choice, especially for anything beyond very short-term use.
Baclofen	Diclofenac	No direct interaction.	Additive CNS depression from baclofen. Standard NSAID risks from diclofenac. High risk if combined with another NSAID.23	Avoid using two different NSAIDs simultaneously (therapeutic duplication) due to compounded GI/renal risk.23
Tizanidine	Celecoxib	No interaction found.32	Additive CNS depression. Tizanidine carries a risk of liver toxicity.24	Celecoxib may have a lower GI risk but still carries cardiovascular warnings.8 Monitor liver function if using tizanidine.
Metaxalone	Meloxicam	No interaction found.28	Additive CNS depression. Risk of serotonin syndrome with metaxalone.33	Metaxalone is contraindicated in severe liver/kidney disease.24
Dantrolene	Indomethacin	No direct interaction.	Additive CNS depression. Dantrolene has a black box warning for fatal hepatotoxicity.24	Dantrolene has numerous contraindications and is generally reserved for severe spasticity or malignant hyperthermia, not routine pain.

Special Considerations for High-Risk Individuals

The risks associated with combining SMRs and NSAIDs are not distributed equally across the population.

For certain groups, particularly older adults and those with pre-existing health conditions, the potential for harm is significantly magnified.

For these individuals, the discussion shifts from simply managing side effects to actively preventing potentially catastrophic events.

Geriatric Patients (Age 65+)

Older adults are uniquely vulnerable to the adverse effects of this drug combination.

The Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, a widely recognized guideline, specifically lists most SMRs as medications to be avoided or used with extreme caution in this population.¹²

The reasons are multifaceted:

• Heightened Sensitivity and Reduced Clearance: As the body ages, liver and kidney function naturally decline. This slows the metabolism and clearance of drugs, causing them to remain in the system longer and at higher concentrations. Consequently, an older adult may experience much more profound effects from a standard dose of an SMR or NSAID than a younger person would.⁶
• The Fall Risk Cascade: The most significant danger for older adults is the dramatically increased risk of falls. The additive CNS depression from the drug combination—causing drowsiness, dizziness, confusion, and poor coordination—can be devastating when combined with age-related frailty, vision changes, or balance issues. A study found that geriatric patients taking muscle relaxants were significantly more likely to visit the emergency department or be hospitalized for a fall or fracture.¹⁸ A fall in an older adult is not a minor event; it can lead to hip fractures, surgery, prolonged immobility, loss of independence, and a marked increase in mortality.
• Magnified NSAID Risks: The risks of NSAIDs are also amplified in the elderly. Age is an independent risk factor for gastrointestinal bleeding, and the kidneys are less resilient to the changes in blood flow caused by NSAIDs. Furthermore, conditions like heart failure and high blood pressure, which are common in this population, can be exacerbated by the fluid retention and cardiovascular effects of NSAIDs.¹⁰

For these reasons, the risk-benefit calculation for the elderly is heavily weighted against the routine use of this combination.

Non-pharmacologic approaches and safer alternatives should always be prioritized.

Patients with Pre-existing Medical Conditions

Individuals with certain chronic diseases are at a much higher risk of serious complications from this combination therapy.

A thorough medical history is essential before prescribing.

• Cardiovascular Disease: Patients with a history of heart attack, stroke, heart failure, or uncontrolled hypertension should use NSAIDs with extreme caution, if at all.³ The SMR cyclobenzaprine should be avoided entirely in patients with arrhythmias or recent heart attack.²⁴
• Gastrointestinal Disease: Anyone with a history of peptic ulcers, gastritis, or GI bleeding is at high risk for a recurrence when taking an NSAID.³
• Liver Disease: Patients with liver impairment must be treated with caution. SMRs specifically associated with liver toxicity, such as dantrolene, tizanidine, and chlorzoxazone, should generally be avoided. Other SMRs that are heavily metabolized by the liver, like cyclobenzaprine and metaxalone, require dose adjustments and careful monitoring.⁷
• Kidney Disease: NSAIDs can be toxic to the kidneys and should be avoided or used with extreme caution in patients with renal impairment.⁶ Certain SMRs, including metaxalone and injectable methocarbamol, are also contraindicated in severe kidney disease.²⁴

Table 4: Risk Profile Summary for High-Risk Patient Groups

Patient Group / Condition	Primary Risk(s) from Combination	SMRs to Use with Caution or Avoid	NSAIDs to Use with Caution or Avoid
Geriatric Patients (65+)	High risk of falls, fractures, confusion, sedation.18	Avoid most SMRs per Beers Criteria (e.g., carisoprodol, cyclobenzaprine, methocarbamol).12	Avoid long-term use. Use with caution due to GI, renal, and cardiac risks.18
Cardiovascular Disease	Worsening heart failure, increased blood pressure, risk of heart attack/stroke.6	Avoid cyclobenzaprine. Use others with caution.	Avoid or use with extreme caution. Diclofenac may carry the highest risk.8
Gastrointestinal Disease	High risk of ulcers, bleeding, perforation.3	Use with standard caution.	Avoid or use with extreme caution. May require co-prescription of a stomach-protecting agent.
Liver Disease	Risk of drug-induced liver injury, impaired drug metabolism.7	Avoid dantrolene, tizanidine, chlorzoxazone. Use others with caution and dose adjustment.	Use with caution, especially with long-term use.
Kidney Disease	Worsening renal function, acute kidney injury.6	Avoid metaxalone, injectable methocarbamol in severe disease.	Avoid or use with extreme caution.

Review of Clinical Practice Guidelines

An examination of guidelines from major medical and regulatory bodies reveals a consistent trend toward a more cautious, patient-centered, and “de-escalated” approach to pain management.

The routine, first-line combination of two systemic drugs like an SMR and an NSAID runs counter to this guiding principle of modern pain care.

American College of Physicians (ACP) & American Pain Society (APS)

The most influential guidelines for non-radicular low back pain come from the ACP, which updated its recommendations in 2017.

The guidance emphasizes a stepped-care approach ¹⁶:

1. First-line Treatment: Physicians and patients should prioritize non-pharmacologic therapies, such as superficial heat, massage, acupuncture, or spinal manipulation.
2. Second-line Treatment: If drug therapy is desired for acute or subacute low back pain, the guidelines recommend selecting NSAIDs or skeletal muscle relaxants. The use of “or” is significant, positioning them as alternative options rather than a required combination.¹⁵
3. Chronic Pain: For chronic low back pain, the ACP recommends NSAIDs as a first-line pharmacologic option if non-drug therapies fail. SMRs are generally not recommended for chronic pain due to a lack of evidence for their long-term efficacy and safety.¹⁵

U.S. Food and Drug Administration (FDA)

The FDA does not issue broad guidelines for combining drug classes but regulates individual products through their approved labeling.

The collective message from these labels is one of risk mitigation.

• The FDA has issued strong warnings about the dangers of combining CNS depressants, particularly the potentially fatal respiratory depression that can occur when SMRs are taken with opioids.³⁶
• The label for cyclobenzaprine highlights the lack of evidence for added benefit when combined with analgesics and includes specific cautions for use in patients with liver problems.⁷
• Labels for combination products containing an NSAID and an opioid, such as SEGLENTIS (celecoxib/tramadol), contain extensive boxed warnings detailing the risks of both drug classes, including addiction, abuse, and serious cardiovascular and gastrointestinal events.³⁷

The FDA’s stance is to ensure that the risks of each component are clearly stated, reinforcing the need for a careful risk-benefit analysis by the prescribing clinician.

Centers for Disease Control and Prevention (CDC)

The CDC’s clinical practice guidelines focus on creating a safer environment for pain management, primarily in the context of reducing the harms of opioid therapy but with principles that apply broadly.³⁹

The guidelines champion a holistic, patient-centered approach that involves clear communication between clinicians and patients about the risks and benefits of all treatment options.

They strongly advocate for the use of non-pharmacologic and non-opioid therapies, urging clinicians to select the safest and most effective treatments for each individual.

This philosophy supports a model where multiple systemic drugs are not the starting point, but are considered only after safer options have been tried and proven insufficient.

Conclusion and Actionable Recommendations

The decision to take a muscle relaxant with an anti-inflammatory drug is complex, with a landscape of conflicting evidence and significant potential risks that vary greatly from person to person.

While the combination is a common clinical practice for the short-term management of acute musculoskeletal pain, its superiority over single-agent therapy is not well-established in the scientific literature.

The potential for additive side effects—most notably central nervous system depression and compounded stress on the gastrointestinal tract, kidneys, and liver—demands a cautious and highly individualized approach.

The evidence strongly indicates that this combination should only be considered for short-term use, typically no longer than two to three weeks, for acute conditions where both inflammation and significant muscle spasm are present.³

It is particularly risky and generally discouraged for older adults and individuals with pre-existing heart, liver, kidney, or gastrointestinal conditions.

Actionable Steps for Patients

This report is designed to empower patients to have a productive and informed conversation with their healthcare provider.

It is not a substitute for professional medical advice.

Before starting or combining any medications, consider the following steps:

1. Provide a Complete Medical History: Ensure your healthcare provider is aware of all your medical conditions, especially any history of heart problems, high blood pressure, stomach ulcers, liver disease, or kidney issues.
2. Disclose All Medications and Substances: Inform your doctor about every medication you take, including prescriptions, over-the-counter drugs (like aspirin or cold medicine), and dietary supplements. It is critically important to be honest about alcohol consumption.
3. Ask Specific, Targeted Questions:

• “Given my specific injury, is a combination of two drugs necessary, or could we start with one first to see if it provides enough relief?”
• “What are the specific side effects I should watch for with this particular pairing of medications?”
• “How will this combination interact with my other existing medical conditions or medications?”
• “What is our plan for the duration of this treatment, and how will we taper off the medications?”

4. Discuss Non-Pharmacologic Alternatives: Ask about evidence-based, non-drug therapies that are recommended as first-line treatments, such as physical therapy, targeted exercises, superficial heat, or massage.¹⁶
5. Know the Warning Signs: Understand the symptoms of serious side effects and know when to seek immediate medical attention. These include:

• Signs of GI Bleeding: Black, tarry stools; vomit that looks like coffee grounds; severe stomach pain.
• Signs of Liver Problems: Yellowing of the skin or eyes (jaundice); dark urine; severe fatigue.
• Signs of Severe CNS Depression: Extreme drowsiness or confusion; difficulty waking up.
• Signs of an Allergic Reaction: Rash, hives, swelling of the face or throat, difficulty breathing.

Ultimately, the safest and most effective treatment plan is one that is tailored to your unique clinical situation.

Never start, stop, or combine medications without the direct guidance of a qualified healthcare provider who can weigh the potential benefits against the clear and present risks.

Works cited

1. Anti-inflammatory drugs and myorelaxants. Pharmacology and clinical use in musculoskeletal disease – PubMed, accessed August 8, 2025, https://pubmed.ncbi.nlm.nih.gov/8784934/
2. The Benefits and Risks of Using Muscle Relaxer and Ibuprofen …, accessed August 8, 2025, https://paramountrecoverycenters.com/the-potential-benefits-and-risks-of-combining-muscle-relaxer-and-ibuprofen-for-pain-management/
3. Can you take cyclobenzaprine and naproxen together? – SingleCare, accessed August 8, 2025, https://www.singlecare.com/blog/cyclobenzaprine-and-naproxen/
4. Can You Take a Muscle Relaxer with Ibuprofen for Pain Relief?, accessed August 8, 2025, https://addictionresource.com/drugs/muscle-relaxers/interactions/
5. Efficacy, acceptability, and safety of muscle relaxants for adults with non-specific low back pain: systematic review and meta-analysis | The BMJ, accessed August 8, 2025, https://www.bmj.com/content/374/bmj.n1446
6. Can I take cyclobenzaprine with ibuprofen? – SingleCare, accessed August 8, 2025, https://www.singlecare.com/blog/cyclobenzaprine-and-ibuprofen/
7. FLEXERIL® (CYCLOBENZAPRINE HCl) Tablets – accessdata.fda.gov, accessed August 8, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/017821s045lbl.pdf
8. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) – StatPearls – NCBI …, accessed August 8, 2025, https://www.ncbi.nlm.nih.gov/books/NBK547742/
9. Watch out for Your Kidneys When You Use Medicines for Pain – National Kidney Foundation, accessed August 8, 2025, https://www.kidney.org/news-stories/watch-out-your-kidneys-when-you-use-medicines-pain
10. ANALGESIC AND MUSCLE RELAXANT, accessed August 8, 2025, https://pdf.hres.ca/dpd_pm/00018716.PDF
11. Muscle Relaxer vs Painkiller | Power – Clinical Trials, accessed August 8, 2025, https://www.withpower.com/guides/muscle-relaxer-vs-painkiller-c902
12. Considerations for the Appropriate Use of Skeletal Muscle Relaxants for the Management Of Acute Low Back Pain – PubMed Central, accessed August 8, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4103716/
13. Muscle relaxers: Types, side effects, safety, and more, accessed August 8, 2025, https://www.medicalnewstoday.com/articles/muscle-relaxers
14. pubmed.ncbi.nlm.nih.gov, accessed August 8, 2025, https://pubmed.ncbi.nlm.nih.gov/8784934/#:~:text=Anti%2Dinflammatory%20agents%20and%20myorelaxants,pain%20such%20as%20rheumatoid%20arthritis.
15. Noninvasive Treatments for Acute, Subacute, and Chronic Low Back …, accessed August 8, 2025, https://www.acpjournals.org/doi/10.7326/M16-2367
16. American College of Physicians issues guideline for treating …, accessed August 8, 2025, https://www.acponline.org/acp-newsroom/american-college-of-physicians-issues-guideline-for-treating-nonradicular-low-back-pain
17. (PDF) Concurrent use of skeletal muscle relaxants and NSAIDs in low back pain management – ResearchGate, accessed August 8, 2025, https://www.researchgate.net/publication/393122693_Concurrent_use_of_skeletal_muscle_relaxants_and_NSAIDs_in_low_back_pain_management_A_critical_review_of_current_evidence_and_back_pain_management_A_critical_review_of_current_evidence_and_future_direc
18. Inappropriate Use of Skeletal Muscle Relaxants in Geriatric Patients – U.S. Pharmacist, accessed August 8, 2025, https://www.uspharmacist.com/article/inappropriate-use-of-skeletal-muscle-relaxants-in-geriatric-patients
19. Carisoprodol and naproxen Interactions – Drugs.com, accessed August 8, 2025, https://www.drugs.com/drug-interactions/carisoprodol-with-naproxen-527-0-1690-0.html
20. Muscle Relaxers: What They Are, Uses, Side Effects & Types – Cleveland Clinic, accessed August 8, 2025, https://my.clevelandclinic.org/health/treatments/24686-muscle-relaxers
21. www.drugs.com, accessed August 8, 2025, https://www.drugs.com/drug-interactions/baclofen-flurbiprofen-lidocaine-topical-with-diclofenac-3574-0-869-0.html#:~:text=Combining%20these%20medications%20may%20increase,through%20the%20stomach%20or%20intestine.
22. Medications – The TMJ Association, accessed August 8, 2025, https://tmj.org/living-with-tmj/treatments/medications/
23. Baclofen / flurbiprofen / lidocaine topical and diclofenac Interactions …, accessed August 8, 2025, https://www.drugs.com/drug-interactions/baclofen-flurbiprofen-lidocaine-topical-with-diclofenac-3574-0-869-0.html
24. Side Effects and Risks of Muscle Relaxers – Spine-health, accessed August 8, 2025, https://www.spine-health.com/treatment/pain-medication/side-effects-and-risks-muscle-relaxers
25. Relaxazone Interactions Checker – Drugs.com, accessed August 8, 2025, https://www.drugs.com/drug-interactions/chlorzoxazone,relaxazone.html
26. Cyclobenzaprine (oral route) – Side effects & dosage – Mayo Clinic, accessed August 8, 2025, https://www.mayoclinic.org/drugs-supplements/cyclobenzaprine-oral-route/description/drg-20063236
27. www.drugs.com, accessed August 8, 2025, https://www.drugs.com/drug-interactions/cyclobenzaprine-with-ibuprofen-758-0-1310-0.html#:~:text=Interactions%20between%20your%20drugs,Always%20consult%20your%20healthcare%20provider.
28. Meloxicam and metaxalone Interactions – Drugs.com, accessed August 8, 2025, https://www.drugs.com/drug-interactions/meloxicam-with-metaxalone-1549-0-1572-0.html
29. pdf.hres.ca, accessed August 8, 2025, https://pdf.hres.ca/dpd_pm/00020441.PDF
30. Can you take Advil with methocarbamol? – SingleCare, accessed August 8, 2025, https://www.singlecare.com/blog/methocarbamol-and-advil/
31. Carisoprodol (oral route) – Side effects & dosage – Mayo Clinic, accessed August 8, 2025, https://www.mayoclinic.org/drugs-supplements/carisoprodol-oral-route/description/drg-20071941
32. Celebrex and tizanidine Interactions – Drugs.com, accessed August 8, 2025, https://www.drugs.com/drug-interactions/celebrex-with-tizanidine-560-284-2205-0.html
33. Metaxalone (oral route) – Side effects & dosage – Mayo Clinic, accessed August 8, 2025, https://www.mayoclinic.org/drugs-supplements/metaxalone-oral-route/description/drg-20071948
34. Dantrolene (oral route) – Side effects & dosage – Mayo Clinic, accessed August 8, 2025, https://www.mayoclinic.org/drugs-supplements/dantrolene-oral-route/description/drg-20063299
35. Learn More: Ten Medications Older Adults Should Avoid or Use with Caution, accessed August 8, 2025, https://www.healthinaging.org/tools-and-tips/learn-more-ten-medications-older-adults-should-avoid-or-use-caution
36. Ask the Pharmacist: Are Skeletal Muscle Relaxants Useful in Management of Chronic Pain?, accessed August 8, 2025, https://www.enlyte.com/insights/article/pharmacy-benefit-management/ask-pharmacist-are-skeletal-muscle-relaxants-useful-0
37. NDA 213426/S-001 Page 4 | FDA, accessed August 8, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213426Orig1s001lbl.pdf
38. Reference ID: 5482803 – accessdata.fda.gov, accessed August 8, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213426s003lbl.pdf
39. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016 | MMWR, accessed August 8, 2025, https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm
40. CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022, accessed August 8, 2025, https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm
41. www.ncbi.nlm.nih.gov, accessed August 8, 2025, https://www.ncbi.nlm.nih.gov/books/NBK547742/#:~:text=NSAIDs%20are%20typically%20divided%20into,meloxicam%2C%20piroxicam)%20anthranilic%20acids%20(