an agent that prevents or relieves spasms (chronic conditions).
causes a response.
prevents a response.
an involuntary contraction of a muscle due to injury or overuse.
an agent that relieves or relaxes acute spasms.
a state of increased tone of a muscle (and an increase in the deep tendon reflexes). For example, with spasticity of the legs (spastic paraplegia) there is an increase in tone of the leg muscles so they feel tight and rigid and the knee jerk reflex is exaggerated.
After completing this chapter, you should be able to
Describe the basic anatomy and physiology of the musculoskeletal system and its relationship to the central and peripheral nervous systems.
List common conditions causing musculoskeletal pain.
Discuss the different categories of skeletal muscle relaxants and state their common uses.
Recognize neuromuscular blocking agents used in surgery or procedures.
State the generic names of widely used skeletal muscle relaxants used to treat muscle pain in the acute setting.
List the general mechanisms of action, therapeutic benefit, and adverse effects of some of the most common skeletal muscle relaxants.
The musculoskeletal system is quite complicated because it consists of so many moving parts—the bones, muscles, joints, and connecting tissues. To begin with the fundamentals, the human body consists of 206 bones that form the skeleton. The skeleton is what gives our body a shape and form. Musculoskeletal pain is one of the most common medical complaints among adult patients. This chapter introduces the basic structure and function of the musculoskeletal system and examines medications that are used to modify its actions and treat some of the conditions that affect it (Figure 12-1).
Just by holding this book, you are using 27 bones in each hand! Bones are connected to each other by ligaments, a dense fibrous band that helps to hold the two structures together and can control or limit movement. Joints are the areas where bones are connected to one another and allow certain movement to occur. This is also an area of the skeleton where injuries frequently occur. Consider the last time you twisted your ankle, which is an example of a common sports injury that happens at a joint.
Basic Anatomy and Physiology
As noted, the human skeleton is made up of 206 bones in varying sizes and shapes. Some, like the bones of the skull and rib cage, are fixed in position to protect the organs they surround and maintain the body’s shape. Others are movable to different extents, ranging from the flexibility of the spinal column to the full motion possible with joints (such as the knee, hip, or elbow). Overlying the bones of the skeleton are more than 600 skeletal muscles (Figure 12-2). There are two other types of muscle, cardiac and smooth muscle, which are not covered in this chapter. Muscles are often attached to the bones of the skeleton by tendons, which are elastic tissue that allow for stretching and contracting. In normal muscle movement, these tendons stretch out like a rubber band, and then can return to their original size and shape. Movement that is sudden or extreme may cause these elastic tendons to be injured, which can result in pain.
Muscle is regulated by the nervous system. Recall from Chapters 4 and 5 that the nervous system of the human body can be broadly divided into two main categories: the central nervous system (CNS—the brain, brainstem, and spinal cord) and the peripheral nervous system (PNS). The PNS can be further subdivided into a somatic component (voluntary control) and an autonomic component (involuntary control). The somatic component consists of sensory and motor neurons that affect primarily skeletal muscle. Nerve impulses transmitted by the somatic nervous system cause muscles to contract and relax; the result affects the movement of the part of the body controlled by that muscle, whether it is the flexing of a joint or the maintenance of a position or posture. When muscles are injured, overused, underused, affected by disease, or when the nerve impulses controlling them are abnormal, difficulty in moving or pain can result.
Mr. P is a 32-year-old pizza delivery man who hurt his low back yesterday while lifting heavy drinks out of his car. He noticed a “pull” on the lower right side of his back after lifting the box, but he now describes his pain as all over and worse when he tries to bend forward. He complains of difficulty sleeping due to his back pain, and when he woke up this morning, he was stiff.
Muscle pain is a common complaint. The most frequent cause of this type of pain is trauma or an injury, such as a sprain or strain. A sprain is an abnormal stretching or tear of a ligament that can result in swelling, pain, and even bruising. A common example of this is a twisted ankle that can result in the sprain of the ligament(s) and may cause pain and swelling of the area on the outside of the ankle. Sometimes it can even cause some bruising, which is evidence of very small tears in the ligament(s) from being overstretched. A strain is an overstretched muscle or tendon that is often twisted, pulled, or even slightly torn. Overuse of a muscle or repetitive use can also cause a muscle strain. Muscle strains can result in pain of the injured muscle as well as the surrounding muscles. Strains may also cause swelling, cramping, or even a muscle spasm. A muscle spasm is a cramp, tightness, or involuntary contraction of muscle. A spasm can occur following a strain, overuse of that muscle, or may occur due to lack of certain nutrients the muscle needs to function.
After a thorough history and physical exam, the physician assistant determines Mr. P has an acute low back muscle strain with a moderate amount of muscle spasm. An NSAID is prescribed along with cyclobenzaprine 10 mg by mouth three times a day. What are the possible adverse reactions to these drugs? Could these affect his work in any way?
Low back pain caused by a muscle strain is an example of a common musculoskeletal complaint. Due to the predominant symptom of pain, the first-line treatment of choice for a muscle strain is usually acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID). The NSAID may be used in a high dose or prescription form or in lower doses readily available in over-the-counter medications, such as ibuprofen. For more serious injuries or for patients whose pain is not relieved by analgesics or anti-inflammatory drugs, short-term use of skeletal muscle relaxants can also be prescribed alone or used as an adjunct to the first-line treatment. The types of muscle relaxants used can vary, but most beneficial are the drugs commonly called spasmolytics due to their effects on the pain–spasm cycle of the injured muscle. If the spasm is decreased, the pain should also be lessened. There is some controversy in the use of muscle relaxants in the setting of low back pain due to their numerous side effects and potential for abuse and dependency. Drowsiness and dizziness are the most common adverse effects in this class of medication.
Skeletal Muscle Relaxants
The category of skeletal muscle relaxants is a broad term and includes drugs from several specific categories. They are grouped based on their mechanism of action or the distribution of medication. For purposes of understanding how they work, these medications can be broken down into two general areas of use: spasmolytics and antispasmodic medications. In acute painful conditions, spasmolytic drugs are often used for the relief of muscle spasm. Antispasmodic medications have antispasticity effects and are usually prescribed to treat chronic conditions causing generalized muscle cramping, increased muscle tone, or spasticity. The final category, neuromuscular blocking agents, contains drugs primarily used for anesthesia in the hospital or operating room setting.
Spasmolytic is a term used to denote the type of medications that are routinely used for the relief of muscle spasm and pain in the setting of acute musculoskeletal injury. This includes two categories of the muscle relaxant medicines: the centrally acting drugs and the miscellaneous skeletal muscle relaxants. Both categories are used mainly in the outpatient setting for the treatment of acute musculoskeletal pain and spasm but may also be ordered for hospitalized patients.
Centrally acting drugs are so called because they exert their effects on the CNS (brain, brainstem, or spinal cord). Not every medication has the exact same mechanism of action, but many of these drugs act at the level of the brainstem and have sedative properties. Specifically, these drugs can affect the motor neuron signal, either by increasing the level of inhibition or reducing the level of excitation. The results of these actions are to decrease the muscle tone and the involuntary movement of the muscles. Most commonly, spasmolytics are used in conjunction with other medicines for the relief of pain and spasm associated with muscle strain or injury. These medicines may be recommended for short-term use in acute musculoskeletal injury. The medications in this category are similar in their effectiveness, and provider preference and medication safety are usually considered when choosing the preferred treatment.
Methocarbamol (brand name Robaxin) is an example of a centrally acting skeletal muscle relaxant. When given orally it begins to take effect in about 30 minutes. Its mechanism of action is not completely known, but it may decrease the number of impulses that get from the spinal cord to the muscle. It also may have some CNS depression, which would account for some of its adverse reactions. Common side effects include dizziness, drowsiness, lightheadedness, headache, and nausea. Methocarbamol is also available as an injectable product, but the other medications in this category are always administered by mouth (see Medication Table 12-1; Medication Tables are located at the end of the chapter).
LOOK-ALIKE/SOUND-ALIKE—The centrally acting muscle relaxant tizanidine has been confused with tiagabine, an anticonvulsant.
The difficulty with centrally acting spasmolytics is twofold: first, they can cause some unpleasant side effects and second, there is potential for abuse or dependency. Most commonly, this class of medication may cause dizziness, drowsiness, lightheadedness, fatigue, dry mouth, or nausea. For this reason, patients should not drive or operate heavy machinery while using these medications. Pharmacologically, several of the individual medicines are similar to other common drug classes such as tricyclic antidepressants and antihistamines, which are also known to cause drowsiness, dry mouth, and dizziness.
Caution is advised when a centrally acting skeletal muscle relaxant is used to treat an older patient (potential for sedation and falls), or a patient with liver or kidney disease (reduced drug clearance and increased drug action/side effects).
Other Skeletal Muscle Relaxants
Medication Table 12-2 lists skeletal muscle relaxants that differ from the centrally acting ones described above in some important ways, including their uses. Of these, only orphenadrine is used for the short-term treatment of musculoskeletal pain. Orphenadrine is in a category by itself. It is a unique medication among skeletal muscle relaxants because it also has an analgesic effect along with its muscle relaxing effect. Its mechanism of action is not fully known, but it is thought to be centrally acting like the medications in the category above. Chemically this medication is very similar to diphenhydramine (Benadryl), which also has many anticholinergic properties. The side effects of this medication are also very similar to the antihistamines, including dry mouth, blurred vision, and urinary retention. It can be given orally or injected.
Mr. P asks if there is anything else he can do to help his back get better. He is anxious about getting back to work as soon as he can.
Because muscle relaxants and analgesics (pain relievers) are frequently used together, several are available as combination products to increase compliance and patient convenience. These are listed in Medication Table 12-3.
Most acute musculoskeletal injuries are self-limiting and resolve on their own. There is some benefit to the application of heat and/or ice to the injured area for 20 to 30 minutes at a time. Patients should be told to use heating pads for limited periods only and cautioned not to fall asleep with a heating pad due to the risk of burns and other injury. Over-the-counter analgesics may also provide temporary relief of the pain associated with injury. Acetaminophen at recommended doses is an appropriate first-line treatment, especially in the setting of gastrointestinal issues. Ibuprofen or naproxen (and other NSAIDs) offer pain relief as well as some additional anti-inflammatory properties, but they must be taken with food to avoid gastric irritation.
Patients are often given a list of stretches or other exercises to help the injured muscles. These exercises usually start out gently and gradually increase in intensity as recovery occurs over days and weeks. Instruction in proper lifting techniques (bending at the knees and keeping the back straight, avoiding twisting and turning while lifting) as well as proper sleeping positions (on the side, with knees flexed) may help reduce the risk of future injury and pain. Patients may benefit from massage to the area. Some providers recommend using ice to massage over painful muscles (holding the ice with a cloth or glove for application). Similar in principle to the application of heat, ice should only be used for 15 to 20 minutes every few hours while awake to avoid the possibility of skin or other tissue damage. Additionally, physical therapists can offer several treatment modalities to aid in the healing of a muscle strain, as well as teach exercises for stretching of the area and prevention of reinjury. Some patients may prefer complementary and alternative treatments for relief of their symptoms—such as herbal remedies for pain, or nontraditional approaches to musculoskeletal problems, such as acupuncture or Rolfing (a form of deep tissue manipulation). Bed rest is not recommended for the treatment of acute low back pain related to a muscle strain.
Use of herbal remedies may sometimes introduce the possibility of drug interactions; they should be documented in the patient’s pharmacy profile. Additionally, it should be noted that patients are increasingly experimenting with CBD (cannabidiol) products for relief of musculoskeletal pain. These preparations also have many potential drug interactions.
Skeletal muscle relaxants that decrease muscle tone and help relieve chronic muscle contraction and spasm are often called antispasmodics. Chronic conditions causing generalized muscle spasticity can be found in many diseases. Following a cerebrovascular accident (CVA or stroke), some patients develop weakness, or asthenia, in one or more extremities and may also have increased muscle tone that can cause the arm (or leg) to contract or be held in flexion. Skeletal muscle relaxants can offer these patients some relief by decreasing the tone and spasm and allowing them to have improved function and possibly less pain.
Cerebral palsy (CP) is a motor disorder that is usually accompanied by some type of spasticity or involuntary movement. The spasticity is related to a malfunction of the upper motor neurons and may have various effects on motor function. Besides spasticity, muscles can be underdeveloped, weak, and have increased muscle tone and reflexes. Spasticity may be a complication of spinal cord injury or multiple sclerosis (MS). Muscle relaxants can be helpful when used properly in the setting of chronic muscle spasm and increased muscle tone.
There are two main medications that fall into this group of antispasmodics. The first medication is dantrolene (brand name Dantrium), which is a direct-acting skeletal muscle relaxant. Essentially, it blocks the release of calcium in the cells of the skeletal muscle. This medication does not have an effect on the CNS but acts at the level of the muscle fibers to weaken the contraction of the muscle. In its oral form it can be used to help decrease muscle spasm in chronic conditions such as CP, MS, and spinal cord injury.
Oral dantrolene is available only as a capsule, but some patients with the chronic conditions described above may have difficulty swallowing a solid dosage form. An appropriate number of capsules may be emptied into an acidic vehicle that has suspending properties, such as Syrup NF or methylcellulose syrup.
A life-threatening condition known as malignant hyperthermia is the result of heightened metabolic activity in the skeletal muscle of susceptible patients exposed to certain anesthetic agents. This is a rare, inherited condition and dantrolene is used for its treatment and prevention. In patients suspected to be at risk, dantrolene may be given by mouth or injection prior to the surgery. When malignant hyperthermia crisis occurs during surgery, an intravenous (IV) dose based on the patient’s body weight is prepared and administered immediately. This is usually followed by additional oral dantrolene doses over the next 3 days.
IV dantrolene doses must be reconstituted immediately before dosing only with sterile water for injection (never dextrose or saline solutions or bacteriostatic water). Reconstituted solutions may be transferred to plastic bags but never to large-volume glass containers and should not be used if they show particulate matter, cloudiness, or discoloration.1
There is a black box warning (the strongest possible requirement of the Food and Drug Administration (FDA) indicating possible serious or life-threatening adverse effects) for this medication due to the incidence of hepatotoxicity. Side effects of this medicine include hepatic impairment, diarrhea, weakness, and somnolence.
The second type of antispasmodic is baclofen (brand names Lioresal, Ozobax) and is considered to be in a separate category called GABA-derivative skeletal muscle relaxant. This drug acts by causing hyperpolarization of the neurons. The activity is mostly focused on the CNS by inhibiting the transmission at the spinal level. In severe cases of spasticity and pain, baclofen can be delivered via an implanted pump that delivers the drug directly into the spinal fluid; this is called intrathecal (IT) administration. Common side effects of baclofen include drowsiness, dizziness, weakness, nausea, and confusion. Caution is used when this medication is prescribed for patients who have seizures or renal disease (Medication Table 12-2).
Neuromuscular blocking agents are given intravenously for a variety of clinical situations, such as surgery or an emergency procedure in which muscle relaxation is desirable. In surgery it is used with anesthesia so that less anesthetic agent is required, which helps to minimize serious side effects. It also helps to lessen a muscle spasm when the breathing tube is inserted into the airway (endotracheal intubation). Because these drugs help muscles relax, the muscle tissue itself can be cut more easily during surgery. Additionally, because they have a quick onset and resolution of action, they are safe and aid in rapid recovery.
Neuromuscular blocking agents can be classified into two main groups: depolarizing blocking agents and the nondepolarizing blocking agents, depending on their activity with respect to the neurotransmitter acetylcholine. The prototype depolarizing blocking agent is succinylcholine, which is commonly utilized as a brief paralyzing agent in emergency departments and operating rooms to assist in rapid-induction endotracheal intubation (placing a breathing tube through a patient’s mouth and into their airway). The mechanism of action begins when succinylcholine occupies the nicotinic receptor and produces a flaccid (relaxed) paralysis. Additionally, because succinylcholine is not broken down by the enzyme that normally breaks down acetylcholine, it remains at the site longer, exhibiting its action of inducing flaccid paralysis. A second phase occurs when the receptor becomes so desensitized that it no longer responds to acetylcholine. Adverse reactions to succinylcholine can include bronchiole constriction, decreased blood pressure, cardiac arrhythmias, and malignant hyperthermia. Another serious adverse reaction can occur in those few individuals who lack the degrading enzyme for succinylcholine as it can take several hours to reverse the response during which time they require mechanical assisted ventilation. Most individuals successfully degrade the drug rapidly, in a matter of several minutes.
The prototype nondepolarizing blocking agent is tubocurarine, which also produces muscle relaxation and decreased muscle tone. It is generally used for longer periods of paralysis and functions by blocking acetylcholine from gaining access to the nicotinic receptor. Adverse effects once again can include bronchiole constriction and decreased blood pressure. Other neuromuscular blocking agents and their characteristics are listed in Medication Table 12-4.
Reversal of neuromuscular blockade induced by rocuronium or vecuronium can be achieved using sugammadex (Bridion).
Skeletal muscle relaxants are helpful in many unique medical settings. The neuromuscular blockers are used in surgery and with procedures, while the other categories of medications may be used in the outpatient setting. Centrally acting skeletal muscle relaxants and orphenadrine can be used effectively in the setting of acute muscle strain. Dantrolene and baclofen are distinctive in that they are more often used with chronic conditions that cause spasticity, such as cerebral palsy (CP) or after a stroke.
U.S. Department of Justice. Office of Diversion Control. Drugs and Chemicals of Concern: Carisoprodol. https://www.deadiversion.usdoj.gov/fed_regs/rules/2011/fr1212_10.htm; https://www.deadiversion.usdoj.gov/drug_chem_info/cyclobenzaprine.pdf#search=cyclobenzaprine. Accessed June 17, 2022.
ADDITIONAL RESOURCES FOR MUSCULOSKELETAL PHARMACOLOGY
For additional information, consider the sources below
Kruidering-HallM, CampbellL.Skeletal muscle relaxants. In: KatzungB ed. Basic and Clinical Pharmacology.14th ed. New York, NY: McGraw-Hill Education/Lange; 2018:474.
Kruidering-HallM, CampbellL.Skeletal muscle relaxants. In: KatzungB ed. Basic and Clinical Pharmacology. 14th ed. New York, NY: McGraw-Hill Education/Lange; 2018:474.)| false
Carisoprodol is subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug. Preparations containing the drug in combination with codeine phosphate are subject to control under the Federal Controlled Substances Act of 1970 as schedule III (C-III) drugs.3
Chlorzoxazone (klor ZOX a zone)
250–500 mg PO TID to QID
Can discolor urine orange to red
Cyclobenzaprine hydrochloride (sye kloe BEN za preen)
Fexmid (7.5 mg tablets)
Amrix (15 mg, 30 mg extended-release caplets)
5–10 mg PO TID
15–30 mg PO daily
Drowsiness is common
While not (as of this writing) a controlled substance, cyclobenzaprine has been the subject of many reports of intentional abuse or misuse3
Metaxalone (me TAX a lone)
800 mg PO TID to QID
Taken on empty stomach; causes less sedation than other agents in this class
Methocarbamol (meth oh KAR ba mole)
Robaxin (750 mg Oral) or 100 mg per mL (IM/IV)
Generic methocarbamol is available in 500 mg or 750 mg for oral use
1,000 mg PO QID
1,000–3000 mg/day IM/IV
May discolor urine black, brown, or green
Tizanidine hydrochloride (tye ZAN i deen)
Zanaflex (2 mg, 4 mg, 6 mg caplet or 4 mg tablet)
8 mg PO q 6–8 hr PRN
May cause hypotension; initial dose is 2 mg PO ×1 carefully titrated upward
Succinylcholine chloride “Sux” (SUX i nil KOE leen) (KLOR ide)
Ultrashort-acting, less than 5 min
May increase intraocular pressure; may cause malignant hyperthermia; may increase potassium levels; may cause cardiac arrhythmias, use in pediatric patients is strictly used for emergency situations only
Atracurium besylate (a tra KURE ree um) (BES i late)
May need higher doses in burn patients
Flushing is a common dermatologic effect; may also cause hives, rash, and bronchospasm
Cisatracurium besylate (sis at ra KURE ee um) (BES i late)
May cause prolonged relaxation, which may be useful in a critical care situation with a patient on mechanical ventilation