Dantrolene: The Forgotten Molecule for Outpatient Spasticity - PracticalPainManagement.com

A case report demonstrates why practitioners should consider dantrolene as a muscle relaxant when treating spasticity in refractory chronic pain and CNS disorders.

Painful muscle spasticity is a chronic complaint among patients with various pain syndromes, particularly those involving upper motor neuron disorders, such as brain and spinal cord injuries, multiple sclerosis, and strokes. Spasticity is defined as a velocity-dependent increase in tone with joint movement that occurs due to excitation of spinal reflex arcs or a loss of descending inhibitory control.¹

Symptoms of Muscle Spasticity

Spasticity can present as muscle hypertonicity and involuntary jerking that affects movement, speech, and gait. A muscle spasm is a sustained muscle contraction that can occur as a result of spasticity or of acute trauma or muscle strain. Although nonpharmacological therapies are favored by most guidelines, adjunctive medications are often required. The American College of Physicians (ACP) guidelines on noninvasive treatments for acute, subacute, and chronic low back pain, for example, include the use of skeletal muscle relaxants if pharmacologic treatment is needed.²

Anti-spastic and antispasmodic medications, collectively referred to as skeletal muscle relaxants, include a variety of medications with differing mechanisms of action. (Image: iStock)

 

Skeletal Muscle Relaxants for Spasticity

Antispastic and antispasmodic medications, collectively referred to as skeletal muscle relaxants, include a variety of medications with differing mechanisms of action. Antispastic medications (eg, baclofen, dantrolene) decrease muscle tone by acting on the central nervous system (CNS) or in the periphery on skeletal muscles. Antispasmodic medications (eg, cyclobenzaprine, methocarbamol) are used to manage pain associated with musculoskeletal conditions.³

There are also agents that fulfill both categories of antispasticity and antispasmodic targets, such as diazepam and tizanidine.⁴ Clinicians often rotate among these various medications depending on the therapeutic effect, adverse effects, and potential for drug interactions with a patient's concurrent medications.

It is beyond the scope of this report to review each of the agents and their reported efficacy, however, prescribers should be familiar with available options for patients who fail or are intolerant to a specific agent.

Painful Muscle Spasticity: A Case Report

A 24-year-old male presented with paraplegia secondary to a gunshot wound that caused a spinal cord injury at T4. He had no sensation in his lower extremities and described intense spasticity with phantom shock-like and burning neuropathic pains. His current regimen included gabapentin 2700 mg per day, dantrolene 25 mg every 8 hours, and duloxetine 30 mg nightly. He failed to benefit from baclofen or cyclobenzaprine. Immediate and extended-release opioids contributed to refractory constipation without providing significant analgesia and were discontinued.

Recommendations were made to further titrate his dantrolene as tolerated, and neuromodulation/intrathecal therapies were discussed. The patient titrated the dantrolene up to 100 mg every 8 hours as needed with improvement of his symptoms in combination with the aforementioned medication regimen.

Discussion of Dantrolene as a Drug for Spasticity

Dantrolene sodium (Dantrium) is often overlooked in the treatment of spasticity despite its skeletal muscle relaxant properties described since 1967.⁵ The clinical indications for dantrolene use include malignant hyperthermia, neuroleptic malignant syndrome, spasticity, and ecstasy intoxication. It is manufactured in both intravenous and oral forms. This antispastic medication is unique because it acts peripherally on the muscle fiber itself in an armamentarium of skeletal muscle relaxants which mostly act centrally on the spinal cord or brain.⁶ It is the only oral peripherally acting antispastic drug approved by the US FDA; however, the potential side effect of generalized muscle weakness and risk of hepatoxicity, particularly with high doses or chronic use, has led to its decrease use.⁷

Dantrolene Benefits for Muscle Relaxation after CNS Injury

Dantrolene is one of the few drugs that acts directly on the skeletal muscle fiber, lessening the excitation-contraction coupling interaction at the individual sarcomere level by binding to the ryanodine receptor, decreasing the actin-myosin interaction within the sarcoplasmic reticulum, inhibiting the release of calcium ions essential to muscle contraction.⁸ In isolated nerve-muscle preparation, dantrolene has been shown to produce relaxation by affecting the contractile response of the skeletal muscle at a site beyond the myoneural junction, directly on the muscle itself.⁹ Animal studies have also shown that dantrolene treatment can prevent lipid peroxidation, augment endogenous antioxidative defense systems, and prevent apoptosis or neurodeficit following traumatic spinal cord injury in the early stages.¹⁰ The drug is more effective than placebo in reducing pain upon maximum voluntary contraction.¹¹ As such, dantrolene is indicated for and has shown benefit in modulating the spasticity resulting from upper motor neuron injury to the CNS.

Dantrolene Contraindications and Adverse Effects

Dantrolene is contraindicated in active hepatic disease, such as hepatitis and cirrhosis. It has a boxed warning about symptomatic fatal or nonfatal hepatitis associated with high doses (greater than 800 mg per day) and long-term use (more than 3 to 12 months). As hepatotoxicity can be enhanced, it is desirable to do liver function studies (SGOT, SGPT, alkaline phosphatase, total bilirubin) at the start of therapy, and routine monitoring is recommended. Because of the potential for liver damage in long-term dantrolene use, therapy should be stopped if benefits are not evident within 45 days. Chronic use has also been associated with pancytopenia.¹¹

The most frequently reported side effects with dantrolene use are drowsiness, dizziness, weakness, general malaise, fatigue, and diarrhea. These are generally transient, occurring early in treatment, and can often be obviated by beginning with a low dose and increasing dosage gradually until an optimal regimen is established.

General muscle weakness can occur as well since it does not selectively target specific muscles. Diarrhea may be severe and may necessitate discontinuation.

Dantrolene Dosage for Spasticity

Dantrolene dosage for spasticity is recommended to start at 25 mg daily for seven days, increasing dosage by 25 mg for seven days at a time until a maximum of 100 mg three times a day in the search for a therapeutic result, and its single dose effect generally lasts up to twelve hours.¹² The total daily dose should not exceed 400 mg. If no further benefit is observed at the next higher dose, dosage should be decreased to the previous lower dose.

Dantrolene Prescribing: Practical Takeaways

Given the difficulty in satisfactorily treating muscle spasm for extended periods of time, it is important to consider the entire spectrum of available therapeutic agents. The case above represents an example of how dantrolene was used in the management of spasticity from a spinal cord injury. Dantrolene has proven to be a unique agent in its peripherally acting mechanism and been found to decrease spasticity and pain in patients with CNS pathologies. This medication should be considered as a muscle relaxant when treating spasticity in refractory chronic pain and CNS disorders.

Last updated on: September 8, 2021

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