Non-Opioid Pharmacology in Pediatric Pain Management

Muscle Relaxants in Pediatric Pain Management

By Jocelyn Wong, MD, Vasili Chernishof, MD and Eugene Kim, MD
Division of Pain Medicine
Children’s Hospital Los Angeles
Keck School of Medicine
University of Southern California
Los Angeles, California

Introduction
Skeletal muscle relaxants (SMRs) are commonly used in pain management for a variety of musculoskeletal conditions from myofascial pain syndromes to muscle spasticity conditions.1,2 Interestingly, the pharmacologic category of skeletal muscle relaxants encompasses a variety of medications that neither share common chemical structure nor similar mechanisms of action. SMRs are grossly classified into two different categories, antispastic or antispasmodic (Table 1).

Table 1: List of common skeletal muscle relaxants

Amongst the commonly prescribed SMRs, only tizanidine and diazepam can be used as both antispastic and antispasmodic muscle relaxants. Antispastic medications work centrally on the spinal cord (baclofen) or directly on the skeletal muscles (dantrolene) to improve muscle hypertonicity and reduce involuntary muscle spasms. Antispastic medications are used for increased muscle tone or stiffness related to cerebral palsy, spinal cord injuries or multiple sclerosis. Antispasmodic medications, such as carisoprodol, cyclobenzaprine, methocarbamol, and metaxalone, work by decreasing muscle spasms through altering conduction in the central nervous system. Antispasmodic medications have been used for conditions such as muscle spasms, post-operative muscle spasms due to surgical manipulation, myofascial pain, fibromyalgia, and tension headaches. 

There is a lack of randomized control studies in the pediatric population and a general paucity of superiority studies in the adult literature.2 Given this, the choice of skeletal muscle relaxants depends largely on extrapolation from adult data­, indication for use (antispastic or antispasmodic), tolerability of side-effects, and potential drug interactions.3,4 In general, all skeletal muscle relaxants will cause some degree of sedation. Amongst the commonly used SMRs, tizanidine and cyclobenzaprine can cause significant sedation, which may be beneficial for patients with nocturnal muscle spasms or insomnia.4

The specific side effects and potential drug interactions of commonly used SMRs are discussed below.

Diazepam
Diazepam binds and stabilizes the GABA-A receptor in a confirmation that increases sensitivity to GABA binding, thus increasing the frequency of chloride channel opening resulting in cell hyperpolarization.5 The use of diazepam has been approved for muscle spasms and as a sedative, hypnotic, and amnesic. As stated previously, diazepam can function as both an antispastic and an antispasmodic muscle relaxant. However, high doses of diazepam are required to treat cerebral palsy spasms.5 Long-term use of diazepam is complicated by tolerance, abuse potential, and sedation. As such, diazepam should be limited to short-term treatment of musculoskeletal conditions.3 Withdrawal symptoms from diazepam include dysphoria, insomnia, diaphoresis, tremor, gastrointestinal upset, and seizures.6 Treatment of overdose syndrome with diazepam requires flumazenil.

Diazepam, as with other benzodiazepines, can have synergistic effects with opioids and enhance respiratory depression and somnolence related to opioids. Diazepam will interact with other sedatives, hypnotics, opioids, barbiturates, antihistamines, alcohol, neuroleptics, anticonvulsants, and selective serotonin reuptake inhibitors.7 Side-effects of diazepam include sedation, memory impairment, and habituation. Diazepam is metabolized by hepatic cytochromes with a minor active metabolite temazepam.7 Due to hepatic metabolism, diazepam should be used with caution in patients with hepatic impairment.

In the acute care setting, diazepam is used to manage painful muscle spasms due to surgical manipulation as part of a multimodal post-surgical pain management plan.8-10 Diazepam is available in intravenous (IV) and enteral (PO) formulations (tablets, capsule, and liquid solution), with 100% bioavailability in the enteral formulation.11 One of the main advantages to using diazepam in the acute post-operative setting is the ease in converting the dose of diazepam between IV and PO formulations.11 Typical dosing of diazepam, whether IV or PO, would begin at 0.05-0.1mg/kg for patients or 2 mg for patients over 20 kg (occasionally, higher doses of 4-5 mg may be needed but titration should occur slowly), three to four times a day for a daily maximum of 12-16mg a day. 3,7,12

Tizanidine
Tizanidine is similar in structure to α2 agonists, such as clonidine.5 Tizanidine functions as a centrally acting skeletal muscle relaxant. It decreases presynaptic and postsynaptic excitatory neurotransmitter release, resulting in decreased locus coeruleus activity.5 Thus, tizanidine can modulate descending motor regulatory pathways. It can function as an antispastic and antispasmodic muscle relaxant. Tizanidine is primarily metabolized by the liver (CYP450 1A2) and is renally excreted.

Due to similar structure to α2 agonists, tizanidine can have sympatholytic effects and cause bradycardia, hypotension, and decreased gastrointestinal motility.13 On a spinal cord level, the α2 receptor agonist effect can be beneficial in certain withdrawal syndromes (such as opioid or alcohol withdrawal) but may cause inadvertent dizziness. Tizanidine can also cause significant sedation, which may limit use. Other notable side-effects include depression, dry mouth, blurred vision, and visual hallucinations.13 If tizanidine is used chronically, rebound hypertension and withdrawal symptoms may occur with abrupt cessation.13 As such, providers should consider tapering tizanidine in patients using tizanidine chronically.

Compared to other commonly prescribed antispastic muscle relaxants, tizanidine is considered better tolerated than baclofen or diazepam.13 However, tizanidine does have numerous drug interactions and regular use of tizanidine can cause elevated liver enzymes. Thus, long-term use of tizanidine will require periodic monitoring of liver function. Tizanidine is considered relatively contraindicated in liver and renal failure.13 As with other muscle relaxants, tizanidine exhibits a synergistic effect with other sedatives. Concomitant use of tizanidine and angiotensin converting enzyme inhibitors (ACEI) has resulted in significant hypotension.

Due to liver metabolism, tizanidine is relatively contraindicated in patients taking medications that require CYP1A2 metabolism. There are numerous medications that require CYP1A2 metabolism including amiodarone, mexiletine, cimetidine, famotidine, oral contraceptive medications, and fluoroquinolones.13 Of note, a small study in 1988 speculated potential protective effects of tizanidine when given in combination with nonsteroidal anti-inflammatories (NSAIDs) for acute lower back pain. The patients who received a combination of the ibuprofen and tizanidine exhibited fewer gastrointestinal side-effects than the patients who received ibuprofen and placebo. Thus, the authors speculated that tizanidine could mediate gastric mucosal protection against NSAIDs.14

Dosing of tizanidine is based on adult dosing regimens that start at 2 mg, initiated at bedtime. The dose can be repeated up to three times a day and titrated based on response and tolerance to side-effects.13

Baclofen
Baclofen has a similar structure as GABA and acts as a specific antagonist to GABA-B receptors. The theoretical mechanism of action of baclofen stems from inhibiting the monosynaptic and polysynaptic reflexes at the level of the spinal cord, thereby inhibiting the release of excitatory neurotransmitters.5 There is FDA approval for the use of baclofen in reversible spasticity and associated pain of spinal cord or cerebral origin. Thus, baclofen has been used for pediatric spasticity due to cerebral palsy and spinal cord injuries. Baclofen can be administered enterally or intrathecally.

One of the main benefits to baclofen is that tolerance does not develop with chronic use. However, baclofen does have numerous side-effects. Baclofen can cause drowsiness, insomnia, dizziness, headaches, weakness, syncope, gastrointestinal upset, constipation, urinary retention, incontinence, paresthesia, respiratory depression, and cardiovascular depression. Baclofen can potentiate the effects of opioids, alcohol, and other central nervous system depressants. Since the bulk of baclofen is excreted unchanged in the urine, baclofen is relatively contraindicated in severe renal impairment. Baclofen can also increase blood sugars and should be used with caution in diabetics. Baclofen is considered unsafe for patients with porphyria. Since baclofen can precipitate bronchospasm, baclofen should be used with caution in asthmatics. Baclofen can cause alterations in liver function, so liver function tests should be monitored with chronic use.15

While tolerance to baclofen does not develop, withdrawal from baclofen can be life threatening. There is a black box warning against abrupt discontinuation of baclofen. Withdrawal symptoms include hyperthermia, tachycardia, seizures, hallucinations, psychosis, and rebound spasticity.15 In rare circumstances, withdrawal from baclofen can cause rhabdomyolysis, multiple organ system failure, and death. To prevent withdrawal, patients on long-term baclofen therapy should be gradually weaned over several weeks before stopping the medication.

Interestingly, while baclofen is widely used to treat pediatric spasticity due to cerebral palsy (CP), there remains insufficient evidence to support or refute the use of oral baclofen for CP spasticity.16,17 Thus, when starting PO baclofen, experts recommend starting oral baclofen at the lowest dose, 2.5-5 mg three times daily.16 The dose can be escalated every three days, to a maximum of 60-80 mg a day.15 If the patient does not show a response within six weeks of starting the maximum dose, or the side-effects are not tolerable, then the PO baclofen trial should be tapered and discontinued. Another antispastic muscle relaxant or intrathecal (IT) baclofen can be trialed.15

While PO baclofen does cross the blood brain barrier, due to the low lipid solubility and hydrophilicity of baclofen, only a small percentage of PO baclofen is able to act on the spinal cord.12 By infusing baclofen into the subarachnoid space, GABA inhibition of baclofen can act directly on the spinal cord, at lower doses than PO baclofen. Thus, IT baclofen can be given at 1% of the PO dose, resulting in a lower incidence of cerebral side-effects and a higher reduction in spastic muscle tone than PO baclofen.12

Intrathecal baclofen has been shown to reduce spasticity in children with CP but is considered a surgical procedure that carries potential catheter-related complications (infection, CSF leaks, catheter malfunction, etc.).16 Prior to placement of an intrathecal baclofen pump, patients must have chronic intractable spasticity, and have been unresponsive or intolerant to a minimum six-week course of PO baclofen therapy.12 In addition, patients must demonstrate a positive response to a test dose of IT baclofen prior to implantation of a continuous infusion pump. Of note, the size of the intrathecal baclofen pump requires a body habitus of at least 15 kgs for placement.12

Dantrolene
Dantrolene inhibits the ryanodine receptor complex resulting in reduced activation by calmodulin and calcium thereby inhibiting the voltage-dependent activation of calcium release in skeletal muscle.5 Dantrolene is approved to treat malignant hyperthermia and spasticity in upper neuronal disorders such as cerebral palsy, spinal cord injury, and multiple sclerosis.

In pediatrics, dantrolene is initiated at 0.5mg/kg daily and increased weekly to a maximum of 12mg/kg/day or 400 mg a day, whichever is lower, in divided doses.17 However, due to the black box warning for hepatotoxicity associated with chronic use, dantrolene is not generally used long-term.18 Side-effects of dantrolene include muscle weakness, drowsiness, dizziness, malaise, and diarrhea.5

Carisoprodol
Carisoprodol is an antispasmodic muscle relaxant with high abuse potential and thus is infrequently prescribed. Side-effects of carisoprodol include dizziness, drowsiness, headache, and rare idiosyncratic reactions that include transient quadriplegia and mental status changes.1 Carisoprodol can cause withdrawal symptoms with abrupt discontinuation.5 Of note, carisoprodol is contraindicated in acute intermittent porphyria.

Cyclobenzaprine
Cyclobenzaprine is similar in structure to tricyclic antidepressants (TCAs). Cyclobenzaprine inhibits 5-HT­2 receptors in the ventral spinal cord, thereby inhibiting tonic alpha-motor neuron excitation.5 Cyclobenzaprine may also inhibit norepinephrine reuptake in the locus coeruleus, thus providing analgesic effects on chronic nerve and muscle pain at the level of the brainstem.19 Cyclobenzaprine is extensively metabolized by the liver and excreted by the kidneys.

Side-effects of cyclobenzaprine include drowsiness, fatigue, dry mouth, headache, dizziness, and blurred vision due to increased intraocular pressure.5 Of note, there is an association of vision damage with long-term use.19 Cyclobenzaprine can cause overdose symptoms of tachycardia, hypertension, widening of the QRS, tremor, slurred speech, confusion, hallucination, and drowsiness.19

Given the structural similarity to TCAs, cyclobenzaprine is contraindicated in patients on or who have taken monoamine oxidase inhibitors (MAOIs) in the past 14 days. If cyclobenzaprine and MAOIs are taken concomitantly, the patient could experience serotonin syndrome, seizures, or even death.19 Other potential drug interactions that may preclude cyclobenzaprine use include other central nervous system depressants (alcohol, barbiturates, etc.), tramadol (due to increased seizure risk), and anti-cholinergic medications.19 Cyclobenzaprine should also be avoided in patients with arrhythmias, conduction disturbances, congestive heart failure, hyperthyroidism and during the recovery period after acute myocardial infarction. There are relative contraindications for cyclobenzaprine in patients with urinary retention, angle-closure glaucoma, or hepatic impairment.19

In pediatrics, cyclobenzaprine had been used as a muscle relaxant prior to the 1990s. However, few studies have reviewed the efficacy of cyclobenzaprine in the pediatric population. There have been small sample pediatric studies from the 1990s that demonstrated efficacy of cyclobenzaprine in treatment of fibromyalgia.20,21 The dosing of cyclobenzaprine is extrapolated from adult dosing regimens, with initiation of cyclobenzaprine at 5 mg at bedtime, escalating up to 10 mg, three times a day.19

Methocarbamol
Methocarbamol is metabolized by the liver, with most of the metabolites excreted in the urine. Notable side-effects include amnesia, confusion, diplopia, dizziness, drowsiness, insomnia, nystagmus, seizures, blurred vision, nasal congestion, metallic taste, rash, bradycardia, hypotension, flushing, thrombophlebitis, dyspepsia, jaundice, and allergic reactions.22 Patients have also noted change in urine coloration, ranging from green to brown to black.1 Overall, methocarbamol can cause significant anticholinergic side-effects that may preclude use.

As with other SMRs, methocarbamol can potentiate respiratory depression if combined with benzodiazepines, barbiturates, or opioids. Methocarbamol is contraindicated in patients with myasthenia gravis as methocarbamol can inhibit pyridostigmine and other acetylcholinesterase inhibitors.22 Thus, methocarbamol can worsen symptoms of myasthenia gravis. Of interest, the urinary metabolites can interfere with 5-hydroxyindoleacetic acid (5-HIAA) and vanillylmandelic acid (VMA) testing.22

Methocarbamol is available in both PO and IV formulation, permitting the transition from IV to PO regimen in the acute post-operative setting. Methocarbamol has been used frequently in the post-operative pain management setting to reduce post-surgical muscle spasms pain. Adult studies as far back as the 1950s demonstrated the use of methocarbamol for severe paravertebral and trapezius muscle spasm after cervical or lumbar laminectomy.23 Recently, methocarbamol was instituted as part of an adult enhanced recovery protocol after lumbar fusion with good effect.24 Dosing of methocarbamol is based off of adult dosing and starts at 10-15mg/kg up to 1000-1500mg, three to four times a day, for the first 48-72 hours. After 48-72 hours, the methocarbamol dose is reduced to no more than 4 grams per day in divided doses.22

Metaxalone
Metaxalone is metabolized in the liver and excreted in the urine, so dose reduction and monitoring are required for patients with renal or hepatic impairment. Of note, when prescribing this medication, a high fat meal will enable more complete drug absorption.25 Side-effects of metaxalone include drowsiness, dizziness, headaches, irritability, gastrointestinal upset, jaundice, leukopenia, hemolytic anemia, hypersensitivity reaction, and anaphylaxis.25

As with other SMRs, metaxalone will potentiate the effects of alcohol, opioids, benzodiazepines, barbiturates, and other central nervous system depressants. In comparison to other SMRs, metaxalone is known to cause less dizziness and drowsiness than other SMRs.3 That said, metaxalone may be preferred when a less sedating agent is desired. 

Metaxalone has not been well studied in the pediatric population; however, adult literature suggests its use in acute low back pain syndrome.25 Given the lack of pediatric data, pediatric dosing is extrapolated from adult data and suggests starting metaxalone at 400mg, four times a day, and increasing to 800 mg four times a day if needed.25

Conclusion
SMRs can be used as part of a multidisciplinary approach to treat musculoskeletal conditions so that patients with painful musculoskeletal conditions may regain function, reduce pain, and improve their quality-of-life. They can be effectively used in conjunction with other multimodal treatment modalities such as cognitive behavioral therapy (CBT), physical therapy, transcutaneous electrical nerve stimulation (TENS), integrative therapies such as acupuncture and yoga, and other medications. Due to the paucity of superiority studies, the choice of SMRs depends on careful consideration of the indication, side-effect profile and potential drug interactions.

References

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