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Drug-induced myopathies

Drug-induced myopathies
Literature review current through: Sep 2023.
This topic last updated: Feb 28, 2023.

INTRODUCTION — Although the precise incidence is unknown, drug-induced myopathy is a common cause of muscle disease. Clinical manifestations range from mild myalgia with no weakness to severe weakness leading, in some cases, to rhabdomyolysis with acute renal failure. Diagnosis relies on having a high clinical suspicion and being aware of the clinical phenotype associated with certain drugs. This topic will review the clinical and laboratory features of drug-induced myopathy.

Rhabdomyolysis and statin myopathy are discussed in detail separately. (See "Rhabdomyolysis: Epidemiology and etiology" and "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Statin muscle-related adverse events".)

DEFINITION — A drug-induced myopathy is defined as the manifestation of myopathic symptoms occurring in patients without prior muscle disease when exposed to certain medications or recreational drugs and improvement or resolution of the symptoms once the offending drug is discontinued. Occasionally, patients may present with isolated elevation of the creatine kinase (CK) level without symptoms.

PATHOGENESIS — Drug-induced myopathy may result from several different mechanisms [1,2]:

Direct myotoxicity — This category includes direct effects on muscle fiber that impair membrane integrity (eg, alcohol, electrolyte imbalance), lysosomal function (eg, chloroquine [CQ], hydroxychloroquine [HCQ]), cytoskeletal organization (eg, colchicine), mitochondrial function (eg, zidovudine), cell metabolism (eg, statins, ranolazine), or protein synthesis (alcohol). Furthermore, intramuscular injections, particularly repeated injections of opiates (eg, heroin, pentazocine), may cause muscle damage with a fibrotic reaction that can result in muscle contractures [3]. Intramuscular injections may also cause myositis ossificans [4]. Inadvertent intraarterial injections may cause ischemic necrosis of muscle tissue that is typically associated with livedoid skin changes or skin infarction (also known as embolia cutis medicamentosa, livedoid dermatitis, and Nicolau syndrome) [5].

Immune-mediated myopathy — Some drugs can trigger the immune system to attack muscle tissue (eg, checkpoint inhibitors, statins).

Indirect muscle damage — This problem can occur by a variety of mechanisms including hypokalemia (eg, diuretics), immobility (eg, drug-induced coma or recreational drugs), hyperkinetic states (eg, delirium tremens or seizures secondary to alcohol), dystonic states (eg, phenothiazines), and hyperthermia (eg, cocaine use).

Drug combinations causing enhanced myopathy — Some drugs may lead to higher serum levels of coadministered drugs because of competition for cytochrome P450 metabolism in the liver. As an example, statins are more likely to result in myotoxicity when combined with medications such as erythromycin, diltiazem, nefazodone, and the azole antifungals [6].

Myopathy may also develop because of the additive myotoxic effects of multiple drugs (eg, colchicine and rapamycin) [7]. An example includes amiodarone muscle toxicity, which results in vacuolar changes on muscle histology when used with statins or colchicine [8,9].

Multiple mechanisms — In some settings, multiple mechanisms may combine to produce muscle damage. As an example, alcohol binges may precipitate hypokalemia, hypophosphatemia, coma, or agitation; in addition, direct muscle toxicity may also be present.

CLINICAL MANIFESTATIONS — The clinical manifestations of a drug-induced myopathy are variable and include myalgia, fatigue, muscle weakness, or myoglobinuria. In mild cases, patients may be incidentally found to have elevated creatine kinase (CK) levels with no associated muscle symptoms. The muscle weakness can involve any skeletal muscle, including ocular, facial, bulbar, respiratory, axial, and limb muscles. Cardiac involvement can occasionally be seen.

In the sections below, we discuss some of the most common drugs associated with myopathy and have grouped them based on whether they cause direct myotoxicity or act via immune-mediated mechanisms. In addition, certain drug combinations may result in a myopathy. (See 'Drug combinations causing enhanced myopathy' above.)

There are additional drugs with rare reports of a myopathy that will not be covered in this review (eg, amiodarone, cyclosporine, vincristine, procainamide, phenytoin).

DRUGS CAUSING DIRECT MYOTOXICITY

Recreational drugs

Alcohol — Alcohol use can lead to both an acute and a chronic myopathy. Alcohol consumption is associated with muscle atrophy affecting both type 2 and, to a lesser extent, type 1 fibers [10]. This is due to a direct effect of alcohol on protein synthesis by impairing translation initiation [11]. Subsequently, messenger ribonucleic acid (mRNA) expression of certain anabolic hormones may be altered, especially insulin/insulin-like growth factor (IGF) signaling, affecting cell metabolism and survival [12]. Furthermore, certain alcohol metabolites, mainly acetaldehyde, can alter calcium release channel gating and muscle contraction [13].

Acute myopathy – Acute alcohol-associated myopathy usually occurs in the setting of alcohol intoxication after massive alcohol consumption. Patients with chronic consumption of alcohol and a chronic alcohol myopathy are at higher risk to develop bouts of acute myopathy with binge drinking [14,15]. Patients may experience recurrent episodes of acute myopathy with recurrent binge drinking. The severity of attacks varies from asymptomatic increases in creatine kinase (CK) to severe myopathy with rhabdomyolysis; acute alcohol-associated myopathy is one of the most common causes of nontraumatic rhabdomyolysis [16]. (See "Rhabdomyolysis: Epidemiology and etiology".)

Presentation – Affected patients present with muscle cramps, tenderness, and, often, swelling. Muscle involvement is usually generalized, although there is a predilection for the calf muscles. CK and other muscle enzymes may be markedly elevated. Peak CK elevation may occur at the time of or several days after admission to the hospital [17]. It has been postulated that phosphate depletion associated with excessive alcohol consumption may be aggravated by refeeding in the hospital without first restoring muscle phosphate, which then leads to further muscle damage. (See "Hypophosphatemia: Causes of hypophosphatemia".)

Clinical course – The typical course of acute alcohol-associated myopathy is full recovery of muscle and renal function after cessation of alcohol intake and management of any complications of rhabdomyolysis, unless underlying chronic alcohol-associated myopathy described below is also present, leading to progressive weakness beyond the acute episode. Recovery of muscle strength can be expected within days to weeks, even in individuals with recurrent attacks.

Diagnostic considerations – As it is a self-limited process, the diagnosis is made based on the clinical presentation in the setting of alcohol intoxication, elevation in CK levels, and confirmation, if needed, by electromyography (EMG). Muscle biopsy in the acute setting in not indicated as it would demonstrate nonspecific muscle fiber necrosis with subsequent degeneration and regeneration. If patients experience persistent symptoms with lack of improvement or further progression beyond the acute episode despite abstinence from alcohol, additional evaluation for alternative causes of myopathy may be considered in the outpatient setting, including referral to a neuromuscular specialist and muscle biopsy.

Chronic myopathy – Chronic alcohol-associated myopathy presents with the gradual onset of diffuse, usually proximal and mild, muscle weakness over a period of weeks to months. Reflexes are commonly preserved. Severe weakness or distal-predominant weakness are unlikely presentations. Diffusely decreased muscle bulk or cachexia is common, even without the presence of a myopathy. Muscle pain and tenderness are usually absent. CK and other muscle enzymes may be normal or only mildly elevated in approximately 60 percent of patients [14].

In a study of 50 individuals with chronic alcohol use disorder, among those who drank more than 13 kg of alcohol per kg of body weight cumulative lifetime dose, it was estimated that more than one-half developed symptomatic chronic myopathy [18]. This dose translates into approximately 12 oz (350 mL) of 86-proof whiskey a day for 20 years in a 70 kg man. No cases of myopathy occurred at lower cumulative doses.

Risk factors – Although chronic alcohol myopathy can occur in isolation, patients with chronic alcoholism may have additional risk factors that affect muscle strength such as malnutrition, sedentariness and deconditioning, electrolyte imbalance, and vitamin deficiency.

Complications – Other sequelae of chronic alcoholism, including peripheral neuropathy, cirrhosis, and Wernicke encephalopathy, are often present. There is also a close clinical and histologic correlation between the presence of chronic myopathy and the development of alcohol-associated cardiomyopathy; both correlate with total lifetime alcohol consumption [19].

Histopathology – On muscle biopsy, the main reported histopathologic finding is that of a mild necrotizing component (presence of necrotic and regenerating fibers) and type 2 fiber atrophy [14,17]. The mild necrotizing component is a nonspecific finding that mainly indicates the presence of a mild active myopathy. Type 2 fiber atrophy can also be seen in connective tissue diseases, malnutrition, corticosteroid use, or deconditioning.

Diagnostic considerations – As the clinical course of chronic alcoholic myopathy may be indistinguishable from other inherited or acquired myopathies, and as there is no diagnostic biomarker for the entity, chronic alcohol myopathy remains a diagnosis of exclusion. Therefore, a referral to a neuromuscular specialist for a more comprehensive evaluation is warranted.

Recovery – Recovery from chronic alcohol-associated myopathy is related to the degree of abstention from further alcohol intake, with those individuals able to abstain completely showing the greatest improvement, those continuing significant intake showing continued deterioration, and those maintaining a controlled lower alcohol intake (less than or equal to 60 g/day) experiencing some improvement in strength but less than in those with total abstinence [20]. In those who abstain, strength begins to improve after several months and continues to improve up to a year [21]. Although some may recover full strength, others may not recover full strength despite continued abstinence [22]. Serial biopsies in patients who abstain have shown significant improvement in the degree of type 2 muscle fiber atrophy over a period of 3 to 18 months; in the same report, those who continued to drink showed an increase in atrophy when rebiopsied 3 to 10 months later [23].

Cocaine — Cocaine is mainly associated with acute muscle injury, often within hours after drug administration, with no reports of a chronic myopathy [24]. Direct cocaine-induced muscle injury may result from the markedly increased sympathomimetic activity induced by cocaine. Severe arterial vasoconstriction can cause skeletal muscle ischemia and infarction in the same manner as cocaine-induced vasospasm causes myocardial, cerebral, skin, or digital infarction [25]. An alternative mechanism is cocaine-induced inhibition of the reuptake of catecholamines at alpha adrenergic receptors, which, in turn, leads to high intracellular calcium levels in muscle cells and to subsequent cell damage and rhabdomyolysis [26].

Presentation – The clinical presentation ranges from asymptomatic CK elevation to massive rhabdomyolysis with acute kidney injury [24,27-29]. Cocaine users with muscle injury usually present to emergency departments with other problems, including delirium, fever, seizures, cardiovascular collapse, or chest pain, and are found incidentally to have muscle involvement [30,31]. In some cases, however, myalgias are an important presenting symptom. Muscle injury can occur after oral or intranasal cocaine use but may be more common after intravenous use or after smoking the alkaloid-free base (crack cocaine) because of the more rapid and higher blood levels of the drug achieved via those routes. Muscle injury can occur after a one-time use of the drug or after repeated use.

CK abnormalities – CK elevation ranges from mild to marked elevations of greater than 50,000 units/L [24]. The patients with the highest CK levels are at greatest risk for acute myoglobinuric kidney failure. These individuals usually, but not always, have additional risk factors for rhabdomyolysis resulting from cocaine use, including marked fever, agitation, hypotension, seizures, coma, or concomitant use of heroin, amphetamines, or phencyclidine (drugs that are also associated with rhabdomyolysis) [30]. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)

Lipid-lowering medications — Lipid-lowering drugs, primarily the statins, are another common cause of myopathy. Muscle injury due to statins, fibrates, and other lipid-lowering drugs is discussed elsewhere. (See "Statin muscle-related adverse events".)

Antiinflammatory and immunosuppressive agents

Chloroquine/hydroxychloroquine — Chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), originally antimalarial drugs, are used in the treatment of systemic rheumatic diseases due to their immunomodulatory effect. CQ/HCQ have been associated with the development of a myopathy or a cardiomyopathy and, to a lesser extent, a peripheral neuropathy [32-34]. CQ/HCQ have affinity to acidic compartments, such as the lysosome, resulting in alteration of the lysosomal function, autophagy, and signaling pathways [32,35]. As a result, there is accumulation of autophagic vacuoles and debris material in tissue over time, including skeletal muscle, cardiac, and retinal tissues [36]. Hence, the development of neuromuscular complications from CQ/HCQ is dose dependent and requires at least a six-month exposure, with a median exposure of nine and a half years [33,37]. Consequently, myopathy is a rare complication of these drugs; one study estimated the incidence to be 1 in 100 patient-years, although this has not been confirmed by others [37].

Myopathy – Patients with myopathy may present with a wide spectrum of clinical presentations consisting of one or a combination of the following: proximal limb, swallowing, respiratory, or axial muscle weakness [33]. Dysphagia is common and often severe, resulting in marked weight loss in some [33]. Muscle enzymes may be elevated in approximately 69 percent of patients (usually not more than three to four times normal) [33]. EMG shows myopathic changes with fibrillation potentials, with a superimposed length-dependent peripheral neuropathy in some. Myotonic discharges can be occasionally seen [33]. Muscle biopsy typically shows a myopathy with autophagic vacuoles and lysosomal dysfunction as witnessed by the accumulation of acid phosphatase material in the vacuoles and in the fiber sarcoplasm (picture 1) [33,36]. Myeloid or curvilinear bodies can be seen in muscle fibers or neural pericytes on electron microscopy when performed [36,38].

Peripheral neuropathy – When present, peripheral neuropathy is usually mild and consists of a length-dependent sensory predominant peripheral neuropathy. In most reported cases of a peripheral neuropathy or a neuromyopathy, the myopathy was the predominant finding [39-41].

Cardiomyopathy – Long-term exposure to CQ/HCQ can cause a cardiomyopathy in isolation or in association with a skeletal myopathy [42-44]. In a small study of patients with CQ/HCQ myopathy, an associated cardiomyopathy was found in 4 of 11 patients (36 percent) who had a cardiac evaluation [33]. When performed, endomyocardial biopsy shows changes similar to skeletal muscle, including degeneration of myocytes, with cytoplasmic vacuoles and granules on light microscopy, and myeloid and curvilinear bodies on electron microscopy [44,45]. The cardiomyopathy is typically restrictive with thickened ventricular walls and with reduced ventricular cavity size [43].

Conduction system abnormalities – In contrast to complications from long-term use of CQ/HCQ, conduction system abnormalities can be seen acutely with short-term use. These drugs block the KCNH2-encoded hERG/Kv11.1 potassium channel and prolong the QT interval, which may result in torsades de pointes [46,47].

Diagnostic considerations – Diagnosis requires a high level of suspicion. The predilection to vital muscles (oropharyngeal, respiratory, and cardiac) highlights the importance of an accurate and timely diagnosis. Longer exposure and higher cumulative doses are associated with higher disability and more common swallowing and cardiac involvement [33].

Symptoms from CQ/HCQ myopathy, especially in the systemic rheumatic disease patient population, may be indistinguishable from those of an immune-mediated myopathy or glucocorticoid-induced myopathy. As management differs and as improvement after discontinuing CQ/HCQ may take some time, the diagnosis is usually established via a muscle biopsy given the distinctive histopathologic features. The presence of fibrillation potentials on EMG and elevated CK level would argue against a glucocorticoid myopathy. Once the offending drug is stopped, improvement is seen in most cases, but usually without going back to normal baseline [32,33].

Glucocorticoids — Glucocorticoids are a common cause of drug-induced myopathy. Long-term use of moderate- or high-dose oral glucocorticoids is associated with a slowly progressive myopathy predominantly affecting proximal muscles. Some patients may develop muscle fatigue and weakness after two to four weeks of high-dose daily glucocorticoid use [48]. The use of parenteral glucocorticoids in the intensive care unit is also a risk factor for the development of critical illness myopathy [49]. Critical illness myopathy and glucocorticoid-induced myopathy are discussed in detail separately. (See "Neuromuscular weakness related to critical illness" and "Glucocorticoid-induced myopathy".)

Colchicine — Colchicine neuromyopathy usually develops after long-term exposure to colchicine (0.5 to 1 mg/day for months to years) but may also develop following short exposure [50-54].

The pathogenesis of colchicine neuromyopathy is likely related to colchicine's known inhibition of microtubule formation, leading to impaired axonal transport in peripheral nerves and to alteration of the muscle cytoskeleton that is necessary for the normal movement of organelles such as the lysosome [50]. Chronic kidney disease leading to increased plasma colchicine levels is considered a risk factor for neuromyopathy [55]. The risk is also increased when colchicine is used concurrently with CYP3A4 inhibitors (eg, macrolide antibiotics, cyclosporin, azoles, and protease inhibitors) [56].

Affected patients typically present with proximal muscle weakness, often more prominent in the lower than upper extremities [50,53]. The associated peripheral neuropathy is usually mild, similar to what is seen with CQ/HCQ neuromyopathy, and can be asymptomatic or causing mild length-dependent sensory symptoms. Percussion and grip myotonia have been reported in a single patient [57].

CK levels are almost always elevated, usually 10- to 20-fold above normal. Nerve conduction studies and EMG usually show myopathic changes with fibrillation potentials, and a superimposed length-dependent, predominantly axonal, peripheral neuropathy, as well as myotonic discharges in some patients [57,58]. The muscle biopsy findings are similar to those seen in CQ/HCQ myopathy with accumulation of autophagic vacuoles and lysosomal dysfunction [50,51].

Muscle weakness resolves and CK levels return to normal within a few days to several weeks after discontinuation of colchicine. The neuropathy usually resolves more slowly.

Similar to other subacute to chronic toxic myopathies, the clinical course and laboratory findings may be indistinguishable from other forms of myopathies, including immune-mediated myopathies. Hence, an accurate diagnosis is crucial, and muscle biopsy is often needed.

Antipsychotic medications — Phenothiazines and other antipsychotic drugs are associated with the neuroleptic malignant syndrome, which is characterized by fever, muscular rigidity, and elevated serum CK indicative of muscle injury. The neuroleptic malignant syndrome is discussed in detail separately. (See "Neuroleptic malignant syndrome".)

Antinucleoside analogues — Zidovudine and other nucleoside reverse transcriptase inhibitors can produce a mitochondrial myopathy with elevated muscle enzymes and weakness. The myopathy typically improves with discontinuation of the drug. However, these older-generation nucleoside reverse transcriptase inhibitors are rarely used, particularly in resource-rich settings. (See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors" and "Diagnosis and differential diagnosis of dermatomyositis and polymyositis in adults", section on 'Differential diagnosis'.)

Chemotherapeutic agents — Chemotherapeutic agents typically cause peripheral nerve toxicity, with only rare case reports of a myopathy, mainly with gemcitabine [59,60]. Exceedingly rare reports describe acute pain and swelling, with increased T2 signal in muscle in areas of previous radiation, precipitated by the use of docetaxel, labeled as radiation recall myositis [61,62]. The development of a myopathy in a patient receiving chemotherapy should raise concern for a paraneoplastic myopathy or critical illness myopathy. Deconditioning and cancer cachexia are often contributing factors to muscle weakness in this patient population.

Others

Ipecac – Ipecac, a derivative of emetine, is used mainly in emergency situations as an emetic for acute poisoning. Chronic use of ipecac syrup by patients with bulimia to cause vomiting and weight loss may cause a proximal myopathy. Patients may also have a cardiomyopathy, and some display skin changes, mimicking dermatomyositis [63-65]. Symptoms usually resolve after discontinuation of the drug. Experimental emetine models demonstrated mitochondrial abnormalities and z-disc abnormalities (nemaline bodies, cytoplasmic bodies, z-disc streaming) in muscle [66,67]. (See "Bulimia nervosa and binge eating disorder in adults: Medical complications and their management", section on 'Skeletal muscle' and "Bulimia nervosa and binge eating disorder in adults: Medical complications and their management", section on 'Ipecac-induced myopathy'.)

RanolazineRanolazine is an anti-ischemic drug used in the treatment of chronic angina. It has been rarely associated with a severe myopathy leading to wheelchair dependency and respiratory failure [68-70]. Presentations include proximal limb weakness, head drop, or respiratory failure [68]. Muscle biopsy shows a lipid storage myopathy (picture 2) [68,69]. Symptoms markedly improve after discontinuation of the drug. It is unclear whether statins have a synergistic effect in these patients, as most patients with angina are also on a statin.

MEK inhibitors – Mitogen-activated extracellular signal regulated kinase (MEK) inhibitors (selumetinib, binimetinib, and cobimetinib) have been associated with a myopathy presenting with head drop [71,72]. Patients improved after discontinuation of the drug.

DRUGS CAUSING AN IMMUNE-MEDIATED MYOPATHY

Immune checkpoint inhibitors — The various immune checkpoint inhibitors, including antiprogrammed cell death 1 (PD-1)/PD-ligand 1 or anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) agents (eg, ipilimumab), have been associated with an aggressive form of immune-mediated myopathy with prominent involvement of oculo-bulbar muscles mimicking myasthenia gravis, often with concomitant myocarditis and significant mortality [73]. This is discussed in detail separately. (See "Rheumatologic complications of checkpoint inhibitor immunotherapy", section on 'Inflammatory myopathies'.)

Statins — Besides toxic myopathy, statin therapy may rarely cause an immune-mediated necrotizing myopathy, associated with the presence of an antibody against 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase in some patients. Creatine kinase (CK) levels are markedly elevated, and muscle histology shows muscle necrosis and regeneration but little to no inflammation [74]. The adverse effects of statins and other lipid-lowering medications on muscles are discussed in detail separately. (See 'Lipid-lowering medications' above and "Statin muscle-related adverse events", section on 'Neuromuscular disorders'.)

Tumor necrosis factor inhibitors — New-onset inflammatory myopathy has been described in a few patients treated with tumor necrosis factor (TNF)-alpha inhibitors [75]. This is discussed separately. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Other conditions'.)

Interferon alfa — Several case reports suggest that immune-mediated myopathy may complicate the use of interferon alfa, including interferon alfa-2b [76-79]. Symptoms typically improve after discontinuation of the drug.

D-penicillamine — Immune-mediated myopathy has been reported in patients treated with D-penicillamine for various conditions, including rheumatoid arthritis [80-84]. Approximately 0.2 to 1.4 percent of patients with rheumatoid arthritis treated with D-penicillamine develop a myopathy [81,85]. However, a limited number of cases are reported in the literature, probably due to the limited use of the drug. Myotoxicity does not appear to be dose or duration dependent [81,82]. In addition to the development of an immune-mediated myopathy, several other autoimmune disorders have been associated with D-penicillamine, including drug-induced lupus, Goodpasture disease, and myasthenia gravis [86].

Affected patients present with symmetric proximal muscle weakness. Axial and swallowing involvement has been reported [81]. A dermatomyositis-like rash has been noted in two patients with rheumatoid arthritis and positive antinuclear antibodies (ANA) [80]. Muscle enzymes may be normal or elevated (<10,000 units/L). Elevated acetylcholine receptor antibodies have been rarely reported [81]. Electromyography (EMG) shows myopathic changes with fibrillation potentials. Muscle biopsy may show perimysial inflammation and, in rare cases, perifascicular atrophy reminiscent of dermatomyositis [81,84].

In most cases, the immune-mediated myopathy resolves completely after the drug is discontinued, and muscle enzymes return to normal within a few weeks to months of stopping the drug [81]. Occasionally, treatment with glucocorticoids is initiated in severe cases or if weakness continues to progress after discontinuing the drug. Some patients have been retreated with the drug without recurrence of myopathy [80].

DIAGNOSIS — A toxic myopathy should be suspected if symptoms of myalgia, fatigue, and muscle weakness can be temporally connected to the administration of a drug or exposure to a myotoxic substance in a patient without a history of pre-existing muscle disease. Improvement or resolution of the symptoms after discontinuation of the drug help confirm the diagnosis of toxic myopathy. In rare cases, re-emergence of the symptoms when the drug is reintroduced further supports the diagnosis. A toxic myopathy should be considered in every case of a myopathy where a cause has not been established. A careful review of the medication list and any over-the-counter supplements should follow.

DIFFERENTIAL DIAGNOSIS — Drug-induced myopathy must be distinguished from other conditions that cause muscle weakness, with or without elevated muscle enzymes. The differential diagnosis is generally the same as that for the idiopathic immune-mediated myopathies and is discussed separately (see "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Differential diagnosis'). Additional considerations include statin-associated rhabdomyolysis, motor neuron disease, myasthenia gravis, and the muscular dystrophies as well as other systemic rheumatic diseases and a variety of inherited, metabolic, drug-induced (especially statin-related), endocrine, and infectious myopathies.

MANAGEMENT PRINCIPLES — The treatment of a toxic myopathy consists of discontinuation of the offending drug and rehabilitative care. In selected cases, such as immune-mediated necrotizing myopathy associated with statin exposure, removal of the offending drug does not typically resolve the weakness and treatment with immunosuppression may be necessary. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Management'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)

SUMMARY

General principles – Drug-induced myopathy is among the most common causes of muscle disease. It ranges from mild myalgias with or without mild weakness to chronic myopathy with severe weakness and to massive rhabdomyolysis with acute renal failure. (See 'Introduction' above.)

Pathogenesis – Drug-induced myopathy may result from several different mechanisms, including direct myotoxicity, immunologically induced muscle injury, indirect muscle injury, or a combination of multiple mechanisms. Some drugs may lead to higher serum drug levels because of competition for Cytochrome P450 metabolism in the liver. Myopathy may also develop because of the additive myotoxic effects of the two drugs. (See 'Pathogenesis' above.)

Drugs causing direct myotoxicity (see 'Drugs causing direct myotoxicity' above):

Alcohol (see 'Alcohol' above)

Cocaine (see 'Cocaine' above)

Lipid-lowering drugs (see 'Lipid-lowering medications' above)

Antimalarials (see 'Chloroquine/hydroxychloroquine' above)

Glucocorticoids (see 'Glucocorticoids' above)

Colchicine (see 'Colchicine' above)

Antipsychotic drugs (see 'Antipsychotic medications' above)

Antinucleoside analogues (see 'Antinucleoside analogues' above)

Chemotherapeutic agents (see 'Chemotherapeutic agents' above)

Ipecac (see 'Others' above)

Drugs causing immune-mediated myopathy (see 'Drugs causing an immune-mediated myopathy' above):

Immune checkpoint inhibitors (see 'Immune checkpoint inhibitors' above)

Statins (see 'Statins' above)

Tumor necrosis factor (TNF) inhibitors (see 'Tumor necrosis factor inhibitors' above)

Interferon alfa (see 'Interferon alfa' above)

D-penicillamine (see 'D-penicillamine' above)

Diagnosis – A toxic myopathy should be suspected if symptoms of myalgia, fatigue, and muscle weakness can be temporally connected to the administration of a drug or exposure to a myotoxic substance in a patient without a history of pre-existing muscle disease. Improvement or resolution of the symptoms after discontinuation of the drug help confirm the diagnosis of toxic myopathy. A toxic myopathy should be considered in every case of a myopathy where a cause has not been established. A careful review of the medication list and any over-the-counter supplements should follow. (See 'Diagnosis' above.)

Management principles – The initial management for most cases of drug-induced myopathies is to discontinue the offending medication. In selected cases, particularly among those in which the mechanism is thought to be immune-mediated, additional treatment with immunosuppression may be necessary. (See 'Management principles' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc L Miller, MD, who contributed to an earlier version of this topic review.

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Topic 5166 Version 26.0

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