INTRODUCTION — Although the precise incidence is unknown, drug-induced myopathy is among the most common causes of muscle disease. Drug-induced myopathy ranges from mild myalgias with or without mild weakness to chronic myopathy with severe weakness and to massive rhabdomyolysis with acute renal failure [1,2]. Over 150 agents have been associated with rhabdomyolysis [3]. This topic will review drug-induced myopathies. 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".)
MECHANISMS — Drug-induced myopathy may result from several different mechanisms [4,5]:
●Direct myotoxicity – Examples include alcohol, cocaine, glucocorticoids, lipid-lowering drugs, antimalarials (which are associated with vacuolar myopathies), colchicine (which is associated with vacuolar myopathies), and zidovudine (which causes a mitochondrial myopathy).
●Immunologically induced inflammatory myopathy – The myopathy associated with D-penicillamine is an example of this mechanism. Statin-associated autoimmune myopathy demonstrates that a single agent may cause myopathy by more than one mechanism.
●Indirect muscle damage – This problem can occur by a variety of mechanisms including drug-induced coma with subsequent ischemic muscle compression, drug-induced hypokalemia (eg, diuretics), drug-induced hyperkinetic states (eg, delirium tremens or seizures secondary to alcohol), dystonic states associated with phenothiazines, hyperthermia related to cocaine use, and the neuroleptic malignant syndrome.
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.
Intramuscular injections, particularly repeated injections of opiates (eg, heroin or pentazocine), may cause muscle damage with a fibrotic reaction that can result in muscle contractures [6]. Inadvertent intraarterial injections may cause ischemic necrosis of muscle tissue that is typically associated with livedoid skin changes or skin infarction (Nicolau syndrome) [7].
DRUGS CAUSING DIRECT MYOTOXICITY
Alcohol — Alcohol use can lead both to an acute myopathy and to a chronic myopathy that differ in alcohol consumption history, in demographics, and in clinical manifestations [8].
Acute myopathy — Acute alcohol-associated myopathy usually occurs in the setting of longstanding alcoholism, within hours after a particularly severe alcohol binge (often one lasting several days). The vast majority of reported cases have been among males with an alcohol use disorder [8]. 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 and acute renal failure [9]. Recurrent episodes of acute myopathy can occur following bouts of binge drinking.
The pathogenesis of acute myopathy probably involves the direct effect of alcohol or of one of its metabolites on muscle cell intermediary metabolism and on muscle cell membrane structure and function that affect transmembrane permeability of ions and water. Hypokalemia and hypophosphatemia, commonly seen in individuals with chronic alcohol use disorder, may potentiate muscle toxicity [8] (see "Hypophosphatemia in the patient with alcohol use disorder"). Although other causes of rhabdomyolysis commonly occur in individuals with alcohol use disorder, including seizures, delirium tremens, and coma, acute myopathy can clearly occur in the absence of any of these factors.
Acute myopathy appears to be related to the dose of alcohol ingested. This may explain why episodes of acute myopathy are more common during drinking binges accompanied by fasting. Starvation decreases alcohol metabolism and results in increased blood alcohol levels [8]. However, acute elevations of serum CK levels and myopathic histologic changes have been induced in normal volunteers given large doses of alcohol in the absence of malnutrition or starvation [10].
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 [11]. 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"). Muscle biopsy demonstrates muscle fiber necrosis with subsequent degeneration and regeneration, which is not specific for acute alcohol-associated myopathy. Thus, biopsy is usually not necessary in patients presenting with what appears alcohol-associated myopathy. However, an exception may be in a patient suspected of having acute alcohol-associated myopathy whose clinical course does not conform to the usual rapid recovery after abstention from alcohol, suggesting an alternative cause of myopathy which would have distinct histologic findings.
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, in which case recovery only back to a previous baseline occurs (see 'Chronic myopathy' below). Recovery of muscle strength can be expected within days to weeks, even in individuals with recurrent attacks.
Chronic myopathy — Chronic alcohol-associated myopathy presents with the gradual onset of diffuse, usually proximal, muscle weakness over a period of weeks to months. Diffuse muscle atrophy is common. Muscle pain and tenderness are usually absent. CK and other muscle enzymes typically are normal or are only mildly elevated, and myoglobinuric renal failure does not occur [8,12].
Females with alcohol use disorder may be at increased risk for chronic myopathy. In one study, for example, females developed myopathy at lower cumulative doses of alcohol than males with alcohol use disorder even when corrected for body weight [13]. Chronic myopathy usually occurs in individuals who are malnourished and have alcohol use disorder, but it has been clearly observed in well-nourished ambulatory patients [14].
The mechanism of chronic alcohol-associated myopathy is incompletely understood. Direct toxic effects of alcohol or one of its metabolites on skeletal and cardiac muscle [15], chronic malnutrition, chronic disuse, and chronic electrolyte abnormalities all are likely to contribute to the onset of weakness and to type II fiber atrophy.
Other sequelae of chronic alcoholism, including peripheral neuropathy, cirrhosis, and Wernicke's 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 [16]. Some patients with chronic myopathy have a history of recurrent acute alcohol-associated myopathy, although the latter does not seem to be a prerequisite for the former.
In one study of 50 individuals with chronic alcohol use disorder, it was estimated that, among those who drank more than 13 kg per kilogram of bodyweight cumulative lifetime dose, more than one-half developed symptomatic chronic myopathy [14]. 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.
Muscle biopsy in individuals with chronic alcohol use disorder almost universally demonstrates some ultrastructural abnormalities on electron microscopy even in the absence of clinically apparent weakness or of myopathic changes on light microscopy [14]. Typical histologic findings in patients with chronic myopathy include increased fat accumulation and type II fiber atrophy that is indistinguishable from changes seen in glucocorticoid-induced myopathy or in disuse atrophy. Muscle fiber necrosis is either absent or minimal, as are inflammatory infiltrates [11].
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 [17]. In those who abstain, strength begins to improve after several months and continues to improve up to a year [18]. Although some may recover full strength, others may not recover full strength despite continued abstinence [19]. Serial biopsies in patients who abstain have shown significant improvement in the degree of type II 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 [12].
Glucocorticoids — Glucocorticoids are a common cause of drug-induced myopathy. Muscle weakness associated with the use of glucocorticoids may complicate parenteral short-term and high-dose use, particularly in the setting of a critical illness. Longer-term use of moderate- or high-dose oral glucocorticoids may produce a more insidious onset of weakness. Critical illness myopathy and glucocorticoid-induced myopathy are presented separately. (See "Neuromuscular weakness related to critical illness" and "Glucocorticoid-induced myopathy".)
Lipid-lowering drugs — 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".)
Cocaine — Muscle injury ranging from asymptomatic CK elevation to massive rhabdomyolysis with acute renal failure has been reported following cocaine use [20-23]. In one report, at least 5 percent of cocaine users presenting to one emergency department had evidence of muscle injury based upon CK elevation [24], and in another, 24 percent of cocaine users presenting to an urban emergency department had CK elevations greater than 1000 units/L [25].
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 [26]. 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 [27].
Cocaine users with muscle injury usually present to emergency departments with other problems, including delirium, fever, seizure, cardiovascular collapse, or chest pain, and are found incidentally to have muscle involvement. 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. The onset of muscle involvement is usually within hours after drug administration [20].
CK elevation ranges from a few times normal to marked elevations of greater than 50,000 units/L. In one report, for example, the mean CK maximum elevation in 39 patients with cocaine-associated rhabdomyolysis was 12,187 units/L [20]. The patients with the highest CK levels are at greatest risk for acute myoglobinuric renal 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 which are also associated with rhabdomyolysis) [24]. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)
Antimalarial drugs — Antimalarial drugs used in the treatment of rheumatoid arthritis and systemic lupus erythematosus have been reported to cause a toxic neuropathy, myopathy, and cardiomyopathy [28]. Most of the case reports have involved chloroquine, but hydroxychloroquine and (in one instance) amodiaquine have also been implicated [29]. 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 [30]. Another study identified 12 cases of hydroxychloroquine neuromyotoxicity that had been reported in the medical literature between 1965 and 1998 [31].
The duration of antimalarial therapy prior to the onset of weakness varies widely from less than one year to more than 10 years [28]. The development of myopathy does not seem to relate to daily dose, as nearly all cases occur with use of standard doses. Decreased kidney function may be a risk factor for the development of myopathy [31].
Antimalarial neuromyopathy is thought to be due to the accumulation of chloroquine or hydroxychloroquine in lysosomes and to the subsequent inhibition of lysosomal enzymes. Phospholipid and glycogen then accumulate in the lysosomes, producing the characteristic myeloid and curvilinear bodies seen on biopsy [28].
Patients with myopathy present with proximal muscle weakness, usually without muscle pain. Peripheral sensory abnormalities, including decreased vibratory sense and absent deep tendon reflexes, may also be present [28]. Muscle enzymes may be normal or mildly elevated (usually not more than three to four times normal). Electromyography (EMG) shows both myopathic and neuropathic changes. Muscle biopsy reveals type II fiber atrophy, evidence of neurogenic muscle fiber atrophy, and vacuoles on light microscopy; electron microscopy shows curvilinear bodies and lysosomal proliferation. Nerve biopsy has shown evidence of a toxic neuropathy; curvilinear bodies have also been demonstrated in neural pericytes [28].
Antimalarial cardiac toxicity may present as a conduction system abnormality or as a cardiomyopathy with congestive heart failure [32,33]. Conduction system abnormalities can be seen acutely with short-term use or as part of a cardiomyopathy from long-term use and large cumulative doses. In the latter instance, the electrocardiogram shows nonspecific T-wave abnormalities, and echocardiography and cardiac catheterization show evidence of restrictive cardiomyopathy with thickened ventricular walls and with reduced ventricular cavity size [34]. Magnetic resonance imaging (MRI) shows evidence of a nonischemic cardiomyopathy (image 1). Endomyocardial biopsy shows changes similar to skeletal muscle, including degeneration of myocytes, which appear enlarged and markedly vacuolated on light microscopy, with cytoplasmic vacuoles and granules (picture 1 and picture 2), and shows the presence on electron microscopy of numerous large, complex, secondary lysosomes with curvilinear bodies and myeloid bodies (picture 3) [35]. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Cardiotoxicity'.)
The diagnosis of antimalarial-induced myopathy or cardiomyopathy is based on the constellation of clinical findings (myopathy, neuropathy, heart failure, or conduction abnormalities), hemodynamic findings (restrictive cardiac physiology), and histologic findings (the presence of lysosomal curvilinear bodies on electron microscopy is highly suggestive of antimalarial toxicity) in the setting of usually long-term antimalarial treatment. The clinical relationship between the cardiomyopathy and skeletal myopathy is variable, ranging from isolated cardiac manifestations to concurrent heart and skeletal muscle disease. If a biopsy is required to establish the diagnosis of cardiac involvement, endomyocardial biopsy would be preferred as it would more definitively establish the antimalarial as the cause of the cardiomyopathy than would an abnormal skeletal muscle biopsy in which the diagnosis of antimalarial cardiomyopathy would be indirectly established.
The clinical response to the discontinuation of the antimalarial is variable. Progression of weakness is halted in most patients within weeks to months after cessation of the offending drug with improvement in clinical and histologic status in some. However, continued progression resulting in worsening weakness, cardiac transplantation, and even death can occur [28,30,35,36].
Antipsychotic drugs — Phenothiazines and other antipsychotic drugs are associated with the neuroleptic malignant syndrome that is characterized by fever and by muscular rigidity and that may have elevation of CK indicative of muscle injury. The neuroleptic malignant syndrome is presented separately. (See "Neuroleptic malignant syndrome".)
Colchicine — Neuromyopathy with colchicine can occur in the setting of acute overdose or even in the setting of chronic administration in therapeutic doses [37,38]. Typically, the patient with chronic colchicine neuromyopathy will have been treated with daily low-dose colchicine (0.5 to 1 mg/day) for months to years; in one documented case, however, myopathy occurred within two weeks of starting colchicine therapy at a dose of 0.6 mg three times daily [39].
The pathogenesis of colchicine neuromyopathy is unknown. It is thought to be related to colchicine’s known effect on microtubule function, leading to impaired axonal transport in peripheral nerves and to alteration of the muscle cytoskeleton that is necessary for the normal movement of lysosomes in the cell [37]. Chronic kidney disease leading to increased plasma colchicine levels appears to be the major risk factor for neuromyopathy [40]. The risk is also increased when CYP3A4 inhibitors, including macrolide antibiotics, cyclosporin, azoles, and protease inhibitors, are used concurrently with colchicine [41]. (See "Treatment of gout flares", section on 'Safety of colchicine'.)
Affected patients typically present with proximal muscle weakness, often more prominent in the lower than upper extremities. CK levels are almost always elevated, usually 10-to 20-fold above normal. EMG and nerve conduction studies document myopathic changes and an accompanying axonal polyneuropathy that is usually asymptomatic or that causes mild sensory symptoms and diminished deep tendon reflexes. Myotonic discharges may be noted in some patients and have been correlated with clinical findings of myotonia [42,43]. Muscle biopsy shows vacuolar changes in muscle cells that are seen best on frozen sections, since the vacuoles are often damaged by paraffin fixation. The vacuoles have been shown to be of lysosomal origin by special stains and by electron microscopy [37,38].
Muscle weakness resolves, and CK levels return to normal within a few days to several weeks after discontinuation of colchicine. The neuropathy resolves more slowly.
Colchicine neuromyopathy may be confused diagnostically with polymyositis. Distinguishing features include the presence of neuropathy by electrodiagnostic testing, as well as the appearance of vacuoles and the absence of inflammation in the muscle biopsy of patients treated with colchicine. In addition, rapid resolution of the myopathy after withdrawal of colchicine strongly supports the diagnosis and helps to avoid the unnecessary use of glucocorticoids (as would be indicated in polymyositis).
Antiretroviral drugs — Zidovudine and other nucleoside reverse transcriptase inhibitors can produce a mitochondrial myopathy with elevated muscle enzymes and with weakness. The myopathy typically improves with discontinuation of the drug. However, these older-generation nucleoside reverse transcriptase inhibitors are uncommonly 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'.)
Ipecac — Chronic use of syrup of ipecac by patients with bulimia to cause vomiting and weight loss may cause muscle damage. In addition to effects on skeletal muscle, cardiotoxicity has also been observed with clinical manifestations of tachycardia, hypotension, and conduction defects [44]. (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'.)
Chemotherapeutic agents — Chemotherapeutic agents can be associated with an acute myopathy localized to sites previously exposed to radiation. Muscle biopsies show necrosis and evidence of a vascular origin of the muscle injury. This phenomenon, termed radiation recall, is typically limited to the skin, but some agents such as gemcitabine more commonly involve muscle [45,46]. Gemcitabine may also cause an acute myopathy in patients who have not been exposed to radiation [47].
DRUGS CAUSING AN IMMUNOLOGICALLY MEDIATED MYOPATHY
Tumor necrosis factor inhibitors — New-onset inflammatory myopathy has been described in a few patients treated with tumor necrosis factors (TNF)-alpha inhibitors [48]. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Other conditions'.)
Interferon alfa — Myositis complicating the use of interferon alfa, including interferon alfa-2b, has been suggested by several case reports [49-52].
Immune checkpoint inhibitors — The various checkpoint inhibitors, including anti-programmed 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 inflammatory myopathy, often with concomitant myocarditis and significant mortality [53]. (See "Rheumatologic complications of checkpoint inhibitor immunotherapy", section on 'Inflammatory myopathies'.)
Statins — Statin therapy may cause an immune-mediated necrotizing myositis associated with the presence of an antibody against 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. This is estimated to occur in 2 to 3 out of every 100,000 individuals treated with a statin. Creatine kinase (CK) levels are markedly elevated, but muscle histology shows muscle necrosis but little to no inflammation as distinct from polymyositis [54]. (See 'Lipid-lowering drugs' above and "Statin muscle-related adverse events", section on 'Neuromuscular disorders'.)
Penicillamine — Several autoimmune disorders have been associated with D-penicillamine, including drug-induced systemic lupus erythematosus, Goodpasture’s syndrome, myasthenia gravis, and an inflammatory myopathy that is clinically and histologically similar to polymyositis. Myopathy has been observed with the use of penicillamine in patients with rheumatoid arthritis, scleroderma, cystinuria, and Wilson’s disease [55,56]. The development of myositis appears to bear no relationship either to daily dose or to the duration of penicillamine therapy [56,57].
Affected patients present with symmetric proximal muscle weakness. Typical dermatomyositis rashes and dysphagia may also be seen [55]. Muscle enzymes are elevated. Electromyography (EMG) shows myopathic changes, and muscle biopsy reveals perifascicular cellular infiltrates, as well as muscle fiber necrosis and regeneration [55,56].
Muscle weakness resolves, and muscle enzymes return to normal within a few weeks to months of stopping the drug plus treatment with high-dose glucocorticoids (40 to 60 mg of prednisone per day). In some cases, clinical recovery has occurred just by stopping penicillamine without adding glucocorticoids [56]. We generally administer glucocorticoids if muscle weakness is severe and if there are no contraindications to their use. Unlike idiopathic dermatomyositis and polymyositis, penicillamine-induced myositis resolves completely and does not recur once the offending drug is discontinued.
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 — 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.)
●Drug-induced myopathy may result from several different mechanisms, including direct myotoxicity, immunologically induced inflammatory myopathy, indirect muscle damage, or a combination of multiple mechanisms. (See 'Mechanisms' above.)
●Drugs that may cause direct myotoxicity include (see 'Drugs causing direct myotoxicity' above):
•Alcohol (see 'Alcohol' above)
•Glucocorticoids (see 'Glucocorticoids' above)
•Lipid-lowering drugs (see 'Lipid-lowering drugs' above)
•Cocaine (see 'Cocaine' above)
•Antimalarials (see 'Antimalarial drugs' above)
•Antipsychotic drugs (see 'Antipsychotic drugs' above)
•Colchicine (see 'Colchicine' above)
•Antiretroviral drugs (see 'Antiretroviral drugs' above)
•Ipecac (see 'Ipecac' above)
•Chemotherapeutic agents (see 'Chemotherapeutic agents' above)
●Alcohol use can lead both to an acute myopathy and to a chronic myopathy that differ in alcohol consumption history, in demographics, and in clinical manifestations. Acute alcohol-associated myopathy usually occurs in the setting of longstanding alcoholism, within hours after a particularly severe alcohol binge. Acute alcohol-associated myopathy is one of the most common causes of nontraumatic rhabdomyolysis and acute renal failure. Chronic alcohol-associated myopathy presents with the gradual onset of diffuse, usually proximal, muscle weakness over a period of weeks to months. Diffuse muscle atrophy is common. (See 'Acute myopathy' above and 'Chronic myopathy' above.)
●Muscle injury ranging from asymptomatic creatine kinase (CK) elevation to massive rhabdomyolysis with acute renal failure has been reported following cocaine use, which is the most common cause of illicit drug-induced medical problems in the United States, including muscle disease. (See 'Cocaine' above.)
●Drugs that may cause an immunologically induced inflammatory myopathy include (see 'Drugs causing an immunologically mediated myopathy' above):
•Tumor necrosis factor (TNF) inhibitors (see 'Tumor necrosis factor inhibitors' above)
•Interferon alfa (see 'Interferon alfa' above)
•Immune checkpoint inhibitors (see 'Immune checkpoint inhibitors' above)
•Statins (see 'Statins' above)
•D-penicillamine (see 'Penicillamine' above)
●Indirect muscle damage can occur by a variety of mechanisms, and, in some settings, multiple mechanisms may combine to produce muscle damage. (See 'Mechanisms' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc L Miller, MD, who contributed to an earlier version of this topic review.
