Introduction
Skeletal muscle relaxants are a heterogeneous group of medications used to treat a variety of conditions characterised by muscle spasms, spasticity, and pain. These drugs act through various mechanisms to reduce muscle tone and alleviate symptoms, thereby improving patient comfort and function. This chapter will provide an in-depth discussion of the pharmacology of skeletal muscle relaxants, including their classification, mechanisms of action, pharmacokinetics, therapeutic uses, adverse effects, and drug interactions. Particular emphasis will be placed on the two main categories of neuromuscular blocking agents: depolarizing and non-depolarizing blockers.
Classification of Skeletal Muscle Relaxants
Skeletal muscle relaxants can be broadly classified into two categories based on their site of action: centrally acting and peripherally acting agents (Katzung & Trevor, 2021).
Centrally Acting Muscle Relaxants
Centrally acting muscle relaxants exert their effects primarily on the central nervous system (CNS), specifically the spinal cord and brain. These agents include benzodiazepines, baclofen, tizanidine, and cyclobenzaprine (Brunton et al., 2018).
Peripherally Acting Muscle Relaxants
Peripherally acting muscle relaxants act directly on skeletal muscles or the neuromuscular junction. This category includes dantrolene, botulinum toxin, and neuromuscular blocking agents (depolarizing and non-depolarizing blockers) (Katzung & Trevor, 2021).
Centrally Acting Muscle Relaxants
Benzodiazepines
Benzodiazepines, such as diazepam, enhance the inhibitory effects of gamma-aminobutyric acid (GABA) by binding to GABAA receptors in the CNS (Katzung & Trevor, 2021). This action leads to increased chloride influx, hyperpolarization of postsynaptic membranes, and reduced neuronal excitability (Brunton et al., 2018). Benzodiazepines are rapidly absorbed orally, with peak plasma concentrations occurring within 1-2 hours. They undergo hepatic metabolism and have a variable half-life ranging from 20-100 hours (Katzung & Trevor, 2021).
Therapeutic uses of benzodiazepines include the treatment of muscle spasms, spasticity associated with neurological disorders, and acute low back pain (Brunton et al., 2018). Common adverse effects include sedation, dizziness, ataxia, and confusion. Long-term use can lead to physical dependence and withdrawal symptoms upon discontinuation (Katzung & Trevor, 2021). Benzodiazepines interact with other CNS depressants, such as alcohol and opioids, potentiating their effects and increasing the risk of respiratory depression (Brunton et al., 2018).
Baclofen
Baclofen is a GABAB receptor agonist that inhibits the release of excitatory neurotransmitters in the spinal cord, leading to reduced muscle tone (Katzung & Trevor, 2021). It is well absorbed orally, with peak plasma concentrations occurring within 2-4 hours. Baclofen undergoes renal excretion, with a half-life of 2-4 hours (Brunton et al., 2018).
Baclofen is primarily used to treat spasticity associated with multiple sclerosis, spinal cord injuries, and cerebral palsy (Katzung & Trevor, 2021). Adverse effects include drowsiness, dizziness, weakness, and gastrointestinal disturbances. Abrupt discontinuation of baclofen can lead to withdrawal symptoms, including seizures and hallucinations (Brunton et al., 2018). Baclofen should be used cautiously in patients with renal impairment, as accumulation can occur (Katzung & Trevor, 2021).
Tizanidine
Tizanidine is an α2-adrenergic receptor agonist that reduces muscle tone by inhibiting the release of excitatory amino acids in the spinal cord (Brunton et al., 2018). It is rapidly absorbed orally, with peak plasma concentrations occurring within 1-2 hours. Tizanidine undergoes extensive first-pass metabolism in the liver and has a half-life of 2-4 hours (Katzung & Trevor, 2021)
Tizanidine is used to treat spasticity associated with multiple sclerosis and spinal cord injuries (Brunton et al., 2018). Common adverse effects include drowsiness, dizziness, hypotension, and dry mouth. Tizanidine can cause liver injury and liver function should be monitored during treatment (Katzung & Trevor, 2021). Concomitant use of tizanidine with CYP1A2 inhibitors, such as ciprofloxacin and fluvoxamine, can increase tizanidine levels and exacerbate adverse effects (Brunton et al., 2018).
Cyclobenzaprine
Cyclobenzaprine is a tricyclic amine that is structurally similar to amitriptyline. Its mechanism of action is not fully understood, but it is thought to act centrally by reducing tonic somatic motor activity (Katzung & Trevor, 2021). Cyclobenzaprine is well absorbed orally, with peak plasma concentrations occurring within 3-8 hours. It undergoes hepatic metabolism and has a half-life of 18-24 hours (Brunton et al., 2018).
Cyclobenzaprine is used to treat acute musculoskeletal pain and spasms associated with conditions such as fibromyalgia and tension headaches (Katzung & Trevor, 2021). Adverse effects include drowsiness, dizziness, dry mouth, and constipation. Cyclobenzaprine should be used cautiously in patients with cardiovascular disorders, glaucoma, and urinary retention (Brunton et al., 2018). It may interact with other CNS depressants and anticholinergic agents (Katzung & Trevor, 2021).
Peripherally Acting Muscle Relaxants
Dantrolene
Dantrolene is a unique muscle relaxant that acts directly on skeletal muscle by inhibiting the release of calcium from the sarcoplasmic reticulum (Katzung & Trevor, 2021). This action reduces the excitation-contraction coupling and leads to muscle relaxation. Dantrolene is poorly absorbed orally, with peak plasma concentrations occurring within 3-6 hours. It undergoes hepatic metabolism and has a half-life of 8-10 hours (Brunton et al., 2018).
Dantrolene is primarily used to treat malignant hyperthermia, a life-threatening condition triggered by exposure to volatile anesthetics and succinylcholine (Katzung & Trevor, 2021). It is also used to manage spasticity associated with cerebral palsy, multiple sclerosis, and spinal cord injuries (Brunton et al., 2018). Adverse effects include muscle weakness, sedation, diarrhoea, and hepatotoxicity. Liver function should be monitored during long-term treatment (Katzung & Trevor, 2021).
Botulinum Toxin
Botulinum toxin is a neurotoxin produced by the bacterium Clostridium botulinum. It acts by inhibiting the release of acetylcholine at the neuromuscular junction, leading to flaccid paralysis (Brunton et al., 2018). Botulinum toxin is administered by local injection into the affected muscles, with effects lasting for 3-6 months (Katzung & Trevor, 2021).
Therapeutic uses of botulinum toxin include the treatment of focal spasticity, cervical dystonia, blepharospasm, and spasmodic dysphonia (Brunton et al., 2018). Adverse effects are usually localized and include pain at the injection site, muscle weakness, and rarely, systemic effects such as dysphagia and respiratory compromise (Katzung & Trevor, 2021). Botulinum toxin should be used cautiously in patients with neuromuscular disorders, as it may exacerbate muscle weakness (Brunton et al., 2018).
Neuromuscular Blocking Agents
Neuromuscular blocking agents (NMBAs) are a group of peripherally acting muscle relaxants that act at the neuromuscular junction to cause paralysis. They are primarily used during surgical procedures to facilitate endotracheal intubation and optimise surgical conditions (Katzung & Trevor, 2021). NMBAs can be classified into two categories based on their mechanism of action: depolarizing and non-depolarizing blockers.
Depolarizing Blockers
Depolarizing blockers, such as succinylcholine, act as agonists at the nicotinic acetylcholine receptors (nAChRs) in the postsynaptic membrane of the neuromuscular junction (Brunton et al., 2018). They bind to and activate the receptors, causing an initial depolarization and muscle fasciculations, followed by a prolonged depolarization that renders the receptors unresponsive to further acetylcholine stimulation, resulting in muscle relaxation (Katzung & Trevor, 2021).
Succinylcholine is the prototype depolarizing NMBA. It is rapidly hydrolyzed by plasma cholinesterase, with a short duration of action (5-10 minutes) (Brunton et al., 2018). Succinylcholine is used for rapid sequence induction of anaesthesia and short surgical procedures. Adverse effects include muscle fasciculations, postoperative myalgia, hyperkalemia, and, rarely, malignant hyperthermia in susceptible individuals (Katzung & Trevor, 2021). Succinylcholine is contraindicated in patients with a history of malignant hyperthermia, severe burns, crush injuries, and neuromuscular disorders such as myasthenia gravis (Brunton et al., 2018).
Non-depolarizing Blockers
Non-depolarizing blockers, such as rocuronium, vecuronium, and cisatracurium, act as competitive antagonists at the nAChRs in the postsynaptic membrane of the neuromuscular junction (Katzung & Trevor, 2021). They bind to the receptors without activating them, preventing acetylcholine from binding and inducing muscle contraction. Non-depolarizing blockers have a slower onset and longer duration of action compared to depolarizing blockers (Brunton et al., 2018).
Non-depolarizing NMBAs are used for longer surgical procedures and to maintain muscle relaxation during mechanical ventilation in the intensive care unit (Katzung & Trevor, 2021). The choice of a specific agent depends on the desired onset and duration of action, as well as patient factors such as renal and hepatic function. Adverse effects include prolonged muscle weakness, residual paralysis, and, rarely, anaphylaxis (Brunton et al., 2018). Reversal agents, such as neostigmine and sugammadex, can be used to antagonize the effects of non-depolarizing blockers and accelerate recovery from neuromuscular blockade (Katzung & Trevor, 2021).
Monitoring and Reversal of Neuromuscular Blockade
Monitoring the depth of neuromuscular blockade is essential to ensure adequate muscle relaxation during surgery and to prevent residual paralysis postoperatively (Brunton et al., 2018). The most common method of monitoring is train-of-four (TOF) stimulation, which involves applying four supramaximal electrical stimuli to a peripheral nerve and assessing the muscle response (Katzung & Trevor, 2021). A TOF ratio (the amplitude of the fourth twitch compared to the first) of less than 0.9 indicates residual neuromuscular blockade and warrants the use of reversal agents (Brunton et al., 2018).
Reversal agents for non-depolarizing NMBAs include acetylcholinesterase inhibitors, such as neostigmine, and selective relaxant binding agents, such as sugammadex (Katzung & Trevor, 2021). Neostigmine inhibits the breakdown of acetylcholine, increasing its concentration at the neuromuscular junction and competitively displacing the non-depolarizing blocker. However, neostigmine can cause muscarinic side effects, such as bradycardia and increased secretions, necessitating co-administration with an anticholinergic agent like glycopyrrolate (Brunton et al., 2018).
Sugammadex is a novel reversal agent that selectively binds to and encapsulates the non-depolarizing blocker, particularly rocuronium, rendering it inactive (Katzung & Trevor, 2021). Sugammadex has a rapid onset of action and can reverse even deep levels of neuromuscular blockade without the muscarinic side effects associated with neostigmine (Brunton et al., 2018). However, sugammadex is more expensive than neostigmine and may not be readily available in all settings (Katzung & Trevor, 2021).
Antispasmodic Agents
Antispasmodic agents are a group of medications used to treat muscle spasms and pain associated with various musculoskeletal conditions. While not strictly classified as skeletal muscle relaxants, they are often used in conjunction with these agents to provide symptomatic relief (Brunton et al., 2018).
Methocarbamol
Methocarbamol is a centrally-acting muscle relaxant with a poorly understood mechanism of action. It may act by inhibiting polysynaptic reflexes in the spinal cord (Brunton et al., 2018). Methocarbamol is rapidly absorbed orally, with peak plasma concentrations occurring within 1-2 hours. It undergoes hepatic metabolism and has a half-life of 1-2 hours (Katzung & Trevor, 2021).
Methocarbamol is used to treat acute musculoskeletal pain and spasms, often in combination with analgesics (Brunton et al., 2018). Common adverse effects include drowsiness, dizziness, and gastrointestinal disturbances. Methocarbamol can cause a brown, green, or blue discoloration of the urine, which is benign and reversible (Katzung & Trevor, 2021). It should be used cautiously in patients with renal or hepatic impairment (Brunton et al., 2018).
Carisoprodol
Carisoprodol is a centrally-acting muscle relaxant that is metabolised to meprobamate, a barbiturate-like sedative (Katzung & Trevor, 2021). Its exact mechanism of action is unknown, but it may act by enhancing GABA-mediated inhibition in the CNS (Brunton et al., 2018). Carisoprodol is rapidly absorbed orally, with peak plasma concentrations occurring within 1-2 hours. It has a half-life of 2-3 hours, while its active metabolite, meprobamate, has a half-life of 10-20 hours (Katzung & Trevor, 2021).
Carisoprodol is used to treat acute musculoskeletal pain and spasms (Brunton et al., 2018). Adverse effects include drowsiness, dizziness, and the potential for abuse and dependence due to its sedative properties. Carisoprodol should be used cautiously in patients with a history of substance abuse and in those taking other CNS depressants (Katzung & Trevor, 2021). Due to concerns about its abuse potential and lack of proven efficacy, carisoprodol has been withdrawn from the market in several countries (Brunton et al., 2018).
Conclusion
Skeletal muscle relaxants are a diverse group of medications used to treat muscle spasms, spasticity, and pain associated with various neurological and musculoskeletal conditions. They can be broadly classified into centrally acting agents, which primarily affect the CNS, and peripherally acting agents, which act directly on skeletal muscles or the neuromuscular junction. Neuromuscular blocking agents, including depolarizing and non-depolarizing blockers, are a specialized subgroup of peripherally acting muscle relaxants used to induce paralysis during surgical procedures.
The choice of a specific skeletal muscle relaxant depends on the underlying condition, desired onset and duration of action, and patient factors such as age, comorbidities, and potential for adverse effects and drug interactions. Careful monitoring of patients receiving these medications is essential to ensure their safe and effective use, particularly in the case of neuromuscular blocking agents, where residual paralysis can have serious consequences.
Antispasmodic agents, while not strictly classified as skeletal muscle relaxants, are often used in conjunction with these medications to provide symptomatic relief for muscle spasms and pain. However, some of these agents, such as carisoprodol, have a potential for abuse and dependence, and their use should be carefully evaluated on a case-by-case basis.
In conclusion, skeletal muscle relaxants play a crucial role in the management of a wide range of neurological and musculoskeletal conditions. A thorough understanding of their pharmacology, including their mechanisms of action, pharmacokinetics, therapeutic uses, adverse effects, and drug interactions, is essential for healthcare professionals to optimize patient outcomes and minimize the risk of complications. As new agents and reversal strategies continue to be developed, it is important for clinicians to stay updated on the latest advances in this field to provide the best possible care for their patients.
Future directions in the pharmacology of skeletal muscle relaxants may include the development of more selective and targeted agents with fewer adverse effects and drug interactions. For example, the discovery of new molecular targets, such as specific subtypes of GABA receptors or novel calcium-regulating proteins in skeletal muscle, could lead to the development of more precise and effective muscle relaxants. Additionally, the use of pharmacogenomics and personalised medicine approaches may help to identify patients who are more likely to respond to specific agents or to experience certain adverse effects, allowing for more tailored and individualised treatment strategies.
Another area of ongoing research is the development of new reversal agents for neuromuscular blocking agents. While sugammadex has revolutionized the reversal of rocuronium-induced neuromuscular blockade, there is still a need for reversal agents that can effectively antagonize other non-depolarizing blockers, such as cisatracurium and atracurium. Moreover, the high cost of sugammadex has limited its widespread use, particularly in resource-limited settings, highlighting the need for more affordable and accessible reversal options.
In addition to their established therapeutic uses, skeletal muscle relaxants may also hold promise in the treatment of other conditions, such as chronic pain syndromes, fibromyalgia, and tension-type headaches. However, more research is needed to evaluate their efficacy and safety in these indications, as well as to determine the optimal dosing and duration of treatment.
Finally, the ongoing opioid epidemic has underscored the importance of developing safer and more effective alternatives for the management of pain and muscle spasms. While skeletal muscle relaxants can be useful adjuncts to pain management, they are not without their own risks and potential for abuse, particularly in the case of centrally acting agents. Therefore, a multidisciplinary approach that encompasses non-pharmacological therapies, such as physical therapy, exercise, and cognitive-behavioural interventions, should be considered in the overall management of patients with musculoskeletal conditions.
In summary, the pharmacology of skeletal muscle relaxants is a complex and evolving field that encompasses a wide range of agents with diverse mechanisms of action and therapeutic applications. As our understanding of the molecular basis of muscle contraction and relaxation continues to expand, so too will our ability to develop more targeted and effective therapies for the management of neuromuscular disorders and musculoskeletal conditions. By staying abreast of the latest advances in this field and applying this knowledge in a patient-centred and evidence-based manner, healthcare professionals can optimize the use of skeletal muscle relaxants to improve patient outcomes and quality of life.
References
Brunton, L. L., Hilal-Dandan, R., & Knollmann, B. C. (Eds.). (2018). Goodman & Gilman’s: The pharmacological basis of therapeutics (13th ed.). McGraw-Hill Education.
Katzung, B. G., & Trevor, A. J. (Eds.). (2021). Basic & clinical pharmacology (15th ed.). McGraw-Hill Education.