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Topics in Geriatric Rehabilitation -  Volume 35 ,  Number 1 ,  72 - 78 -  Copyright (c) 2019 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/TGR.0000000000000217
Clinically Relevant Drug-Induced Myopathies
Annie Burke-Doe ,  PT, MPT, PhD
Clinically identifed myopathies can occur with administration
of medications such as statins, glucocorticoids, antibiotics,
antirheumatics, and retinoids. While the frequency of
drug-induced myopathies is unclear, they are an important
group of disorders in anyone presenting with muscular
symptoms and should be considered in patients with
symptoms ranging from mild myalgia or muscle cramping to
profound muscle weakness without a known etiology. Certain
medications are commonly associated with myopathy and
frequently prescribed (glucocorticoids, statins); a few are
more likely to occur with exercise, whereas others have
myopathy as a rare side effect. Developing a greater
understanding of underlying mechanisms and symptoms of
drug-induced myopathy can promote enhanced awareness,
early recognition, and improved patient care because many
drug-induced myopathies are potentially reversible at early
stages.
Key words: drug-induced myopathy,  statin myopathy,  toxic
myopathy
M
edications can cause adverse drug reactions,
including clinically identified muscle disorders
and toxicity. It is estimated that more than
1 million individuals are seen in hospital emergency depart
ments for adverse drug events each year in the United
States.1 Drug-drug interactions are responsible for nearly
3% of all hospital admissions2 and 4.8% of admissions in
the older adults . 3 Duke et al 4 used data mining of electronic
medical records on 2.2 million patients throughout the
state of Indiana and found 817 059 patients with medica
tion records that included the demographic variable effect
of "myopathy." Among these, 7.2% experienced myopathic
events.4 Five drug interaction pairs were also identifi ed
(loratadine [Claritin], simvastatin [Zocor]), (loratadine
[Claritin], alprazolam [Xanax]), (loratadine [Claritin],
duloxetine [Cymbalta]), (loratadine [Claritin], ropinirole
[Requip]), and (promethazine [Phenergan], tegaserod
[Zelnorm]) and when taken together showed a signifi 
cantly increased risk of myopathy. 4 Drug-drug interactions
are thought to be related to 2 major drug metabolism pro-
Author Affi liation: West Coast University, Los Angeles, California.
The author has disclosed that she has no signifcant relationships with, or
fnancial interest in, any commercial companies pertaining to this article .
Correspondence: Annie Burke-Doe, PT, MPT, PhD, West Coast University,
590 N Vermont Ave, Los Angeles, CA 90004 ( aBurke-Doe@westcoast
university.edu ).
teins found in the liver, cytochrome P450 3A4 and
cytochrome P450 2D6. Cytochrome P450 proteins are a
super family of monooxygenases that catalyze many reac
tions involved in drug metabolism. 5 The exact etiology of
myopathy is unclear and many mechanisms have been
hypothesized, including reduced production of coenzyme
Q10 (ubiquinone), increased cholesterol uptake, changes
in metabolism of fat, decreased sarcolemma, failure to
restore damaged protein in skeletal muscle, decreased pre
nylated protein production and phytosterols, disrupted
metabolism of calcium in muscle tissue, decreased sarco
plasmic reticular cholesterol, and inhibition of selenopro
teins synthesis.6
Muscle tissue is a preferred target for many drugs and
is prone to adverse drug reactions because of its high
exposure (increased mass and metabolism) to circulating
drugs. 7 Many drugs used for therapeutic interventions can
cause drug-induced or toxic myopathy, which is defi ned as
the acute or subacute manifestation of myopathic symp
toms ( Table 1 ) such as muscle weakness, myalgia, creatine
kinase (CK) elevation, or myoglobinuria that can occur in
patients without muscle disease when they are exposed
to certain drugs. 8,9 Functionally, patients may have diffi 
culty with tasks requiring proximal muscles such as rising
from a chair, climbing stairs, or lifting objects. Some drug-
induced myopathies are associated with neuropathy. 10 Cli
nicians who work with patients with muscle complaints or
acquired weaknesses must also integrate an understanding
of prescription and nonprescription medication regimens
with consideration of the impact on health, impairments,
functional limitations, and disabilities.11 A limited review of
medications with a known association of myotoxicity and
the practical implications for the rehabilitation professional
is outlined.
CLASSIFICATION OF DRUG-INDUCED
MYOPATHY
Myotoxic agents can cause myopathy by several different
mechanisms including (a) directly affecting a muscle orga
nelle; (b) altering antigens, thereby inducing immunologi
cal or inflammatory reactions; and ( c) inducing systemic
effects such as electrolyte disturbances, nutritional depriva
tion, or malabsorption, which secondarily affect muscle
function.9 Drug-induced myopathies can be classifi ed
according to the presence or absence of muscular pain and
associated neuropathy ( Table 2 ) or according to histology
( Table 3 ). Overall, several criteria for reporting drug-induced
myopathy are recommended12: (a) lack of preexistent
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TABLE 1 Clinical Manifestations of Drug-Induced Myopathies
Myalgia
Muscle pain, stiffness, or cramps without neurological signs
Myotonia
Delayed relaxation of skeletal muscle after a voluntary contraction
Painless proximal myopathy
Characterized by muscle weakness
Painful myopathies
With drug-induced polymyositis
Without polymyositis
Focal myopathy
Focal area of damage due to injections
Myokymia or rhythmic rippling of muscles
Widespread myokymic discharges seen on the electromyogram
Hypokalemic myopathy
Weakness of muscles due to drug-induced hypokalemia
Mitochondrial myopathy
Inhibition of mitochondrial DNA and characterized by ragged red f bers
Rhabdomyolysis
Acute muscle necrosis with myoglobinuria and systemic complications
Malignant hyperthermia
A severe reaction that can occur with medications used during general anesthesia
among those who are susceptible; symptoms include muscle rigidity, high fever,
and a fast heart rate
Secondary effects of myopathies
Renal shutdown in rhabdomyolysis
Compartment syndromes due to myositis
muscular symptoms, (b) a free period between the
beginning of the treatment and the appearance of symp
toms, (c) lack of another cause accounting for the myopa
thy, and ( d) complete or incomplete resolution after with
drawal of the treatment. Rechallenge of the treatment is
often not advisable because of the risk of a serious relapse. 12
Rechallenge is used in some cases such as statins for fur
ther distinguishing the causality of muscle pain.13 The exact
mechanisms by which drugs cause myopathies are still
being elucidated. Some cases may be due to metabolic
changes, whereas others may be immune mediated. Nev
ertheless, the aspect these conditions have in common is
regression of the myopathy with the discontinuation of the
drug. A detailed drug history is essential in all patients with
myopathic symptoms that would include not only the
usual suspects such as statins and glucocorticoids ( Table 4 )
but also therapeutic agents whose full adverse effect pro
file is unknown and for any combination of potentially
myotoxic agents (synergistic myotoxicity14).
MYOPATHY FROM LIPID-LOWERING AGENTS
Hyperlipidemia is a potent risk factor for atherosclerosis
and coronary heart disease. 15 Statin therapy has been asso
ciated with muscle problems in approximately 10% to 15%
of patients treated in clinical practice, but muscle problems
have rarely been reported in controlled clinical trials. 16 The
difference in clinical experience versus clinical trials is
thought to be related to failure to query subjects, imprecise
definitions of muscle states, placebo effects (side effects
mentioned in an informed consent), the run-in phase of
the trial, different patient populations, and different statin
types.16 The National Lipid Association Muscle Safety Expert
Panel describes the spectrum of statin-associated muscle
toxicity to include myalgia, myopathy, myonecrosis, and
TABLE 2 Drug-Induced Myopathy Classified by the Presence or Absence of Pain

Medication
Painless myopathies
 Without neuropathy
Corticosteroids
With neuropathy
Colchicine, chloroquine, and hydroxychloroquine
 Myasthenic syndromes
D-Penicillamine, antibiotics, -blockers
Painful myopathies (may or may not be associated with neuropathy)
 Polymyositis
D-Penicillamine, cimetidine, zidovudine
Myopathy without polymyositis
Clofbrate, statins, cyclosporine
 Neuromyopathies-eosinophilia-myalgia syndrome
Drug combinations inducing myopathy
A fbrate and a statin or cyclosporine and colchicine
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TABLE 3 Drug-Induced Myopathy Classified by Histology

Medication
Vacuolar myopathy
Colchicine, chloroquine, amiodarone, cyclosporine, drugs causing hypokalemia and lipid-
lowering agents
Mitochondrial myopathy
Zidovudine (AZT), f aluridine, germanium
Necrotizing myopathy
Vincristine, statins, f brates, -aminocaproic acid
Inf ammatory myopathy
Statins, D-penicillamine, -interferon, intramuscular gene therapy
Thick-flament loss myopathy
Critical illness neuromyopathy
Type II fber myopathy
Steroids, systemic effects of cancer
Myofbrillar myopathies
Emetine/ipecac poisoning
clinical rhabdomyolysis. Symptoms are described as mus
cle soreness, stiffness, tenderness, and cramps with or
shortly after exercise. 17 Clinical and genetic predictors of
risk are included in Table 5 .
All classes of lipid-lowering agents have been implicated
in muscle toxicity, 18 and they are considered the most
commonly studied and well-recognized myotoxic agents.8
Agents include fibrates, which promote the secretion of
low-density lipoproteins (clofibrate [Atromid], gemfi brozil
[Lopid]); statins, which inhibit 3-hydroxy-3-methylglutaryl
TABLE 4 Drugs Associated With Myopathy
Lipid-lowering agents
 Statins
 Fibrates
 Nicotinic acid
 Ezetimibe
Glucocorticoids
Prednisone and prednisolone
 Methylprednisolone
 Dexamethasone
 Inhaled steroids
Antirheumatics
 Colchicine
 Chloroquine
 Hydroxychloroquine
Cardiovascular drugs
 Amiodarone
 Perhexiline
Other drugs
 Emetine
-Aminocaproic acid
 Etretinate
 Zidovudine
-Interferon
D-Penicillamine
 Streptokinase
coenzyme A (HMG-CoA), the rate limiting step in the for
mation of cholesterol (HMG-CoA reductase inhibitors
[Crestor, Lipitor]); niacin, which reduces secretion of low-
density lipoproteins (nicotinic acid [Niacor]); and ezeti
mibe (Zetia), which inhibits intestinal absorption of choles
terol. Most patients complain of muscle pain, tenderness,
and weakness when myopathy occurs. Muscle pain is often
related to exercise,18 and patients may have proximal weak
ness. In severe reactions, it may proceed to rhabdomyoly
sis with elevations in serum CK levels ( >3 times baseline)
and myoglobinuria, which are indications for stopping the
drug.
Newer guidelines have been established by the National
Lipid Association Muscle Safety Expert Panel 17 as it relates
to stain therapy and physical activity because statins are
known to be less tolerated in physically active individuals.19
In the prediction of muscular risk in the observational con
ditions study, incidence of muscle pain with statin therapy
increased with the level of physical activity from 10.8% in
those engaging in leisure-type physical activity to 14.7% in
those regularly engaging in vigorous activity, suggesting
that statin-associated muscle side effects are provoked by
physical activity. 20 The task force recommends that physical
activity should be assessed at baseline of statin therapy ini
tiation and taken into consideration when assessing mus
cle complaints. Physical therapists can assist in determi
nation of baseline strength, exercise, and physical activity
ability in this patient population using patient history and
measures such as therapy initiation, dose, proposed statin
myalgia inventory, pain inventory (McGill Pain Question
naire,21 Short-Form Brief Pain Inventory 22), strength testing
(isokinetic dynamometer), aerobic testing, and temporal
patterns of pain onset.
Finally, statins have some off-label use that may impact
rehabilitation. Relapsing and remitting multiple sclerosis
(MS), an immune-mediated, chronic infl ammatory disease,
is one such pathology in which physicians are using statins
as an adjuvant to treatment.23 Hydroxycholesterol and
cholesterol precursors may be possible markers for neu
rodegeneration and demyelination in MS, suggesting the
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TABLE 5 Clinical Predictors of Risk
Genetic Determinates of Risk
Older age
Candidate gene studies (pharmacokinetic candidate genes,
pharmacodynamic candidate genes)
Asian race
Genome-wide associated studies (linkage studies in families,
genome-wide associated studies in unrelated individuals)
Gender (females > males)
Comorbidities (hypothyroidism, hyperuricemia, alcohol
overconsumption)
Statin dose
History of muscle pain with another lipid-lowering therapy
Family history of muscle symptoms due to lipid-lowering agents
Concomitant mediations (CYP3A4 enzyme in liver with
simvastatin [Zocor], inhibitors of CYP3AF enzyme in liver
and SLCO1B1 gene included azole antifungals [Dif ucan],
ritonavir [Norvir], verapamil [Calan], and diltiazem
[Cardizem]; gemf brozil [Lopid])
role for statin drugs. 24 In addition, statins may possess anti-
inflammatory and immunomodulatory effects (ie, inhibit
ing lymphocyte function, the entry of T cells into the cen
tral nervous system, and T-cell activation; the suppression
of secretion of numerous infl ammatory mediators). 25 The
use of adjunctive simvastatin therapy (with interferon- )
in the management of relapsing and remitting MS has
been evaluated in a limited number of controlled trials,
demonstrating conflicting results of either moderate to no
benefi t. 26,27 Two meta-analyses of statins (atorvastatin and
simvastatin) examining the same trials found that there is
no benefit of statins regarding MS relapse rates, disease
progression, or change in disability scores.28,29
MYOPATHY FROM GLUCOCORTICOIDS
Glucocorticoids
(dexamethasone,
hydrocortisone,
methylprednisolone) are a type of corticosteroid hor
mones released from the adrenal gland that are known
for their anti-inflammatory and immunosuppressive
effects. Corticosteroids were introduced into clinical
practice in 1948; in 1958, Dubois30 reported the fi rst
patient with myopathy resulting from iatrogenic corti
costeroids. Corticosteroid-induced myopathy is charac
terized by proximal muscle weakness without pain and
can occur in acute and chronic forms. Corticosteroid
myopathy is considered the most common type of drug-
induced myopathy, with nearly 60% of patients with
Cushing syndrome having muscle weakness and atro
phy. 8 The cause of the condition is believed to be endog
enous or exogenous production of corticosteroid, which
can be the result of an adrenal tumor (endogenous) or
the steroid treatment (exogenous) of asthma, chronic
obstructive pulmonary disease, and infl ammatory
processes such as polymyositis, connective tissue disor
ders, and rheumatoid arthritis. 31 Glucocorticoid-induced
muscle weakness and atrophy affect mainly fast-twitch
glycolytic muscle fibers (type IIb fi bers) 32 and are believed
to be due to suppressed protein synthesis and growth,
enhanced proteolysis, and apoptosis induction.33-35 Many
commonly used glucocorticoids can cause myopathy,
but fluorinated glucocorticoid preparations, such as dex
amethasone, are implicated more often. 32,36
Clinical presentation of chronic forms includes an
insidious onset of muscle weakness that progresses gradu
ally. 37,38 The condition develops after prolonged adminis
tration of prednisone at a dose of 40 to 60 mg/d.39 Onset
of weakness can vary and has been found to occur within
weeks to years following initiation of corticosteroid admin
istration.31 Weakness is more severe in the pelvic girdle
than in the upper extremities. Rarely are distal muscles
affected. Chronic myopathy functional complaints may
include difficulty with sit to stand, negotiating stairs, and
performing reaching activities. Several studies have shown
involvement of the respiratory muscles (diaphragm); thus,
pulmonary symptoms may be present. 40
Acute forms such as critical illness myopathy have been
reported in critically ill patients treated with high-dose
intravenous corticosteroid and nondepolarizing neuro
muscular junction blockers in the intensive care unit and
are thought to be a mechanism of intensive care unit-
acquired weakness.41 The acute form is less common, is
associated with rhabdomyolysis, and occurs abruptly while
the patient is receiving high-dose corticosteroids. 31 Patients
may develop weakness both proximally and distally in the
limbs from primary muscle involvement. The myopathy
can coexist with a neuropathy. 42
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Page 5
ANTIBIOTIC-INDUCED MYOPATHY
Fluoroquinolones (FQs) are widely prescribed antimicro
bial agents acting as direct inhibitors of DNA synthesis and
are used to treat bacterial infections.43 Fluoroquinolones
approved for use in the United States include ciprofl oxacin
(Cipro), levofloxacin (Levaquin), moxifl oxacin (Avelox),
ofloxacin (Floxin), and delafloxacin (Baxdela). In 2016, the
Food and Drug Administration provided a safety warning
that FQs are associated with disabling and potentially per
manent side effects, affecting the tendons, muscles, joints,
nerves, and central nervous system, that can occur
together in the same patient.44 The warning label also rec
ommends discontinuing FQ use at the first sign of unusual
joint or tendon pain, muscle weakness, a "pins and nee
dles" tingling or pricking sensation, numbness in the arms
or legs,44 and refraining from exercise until the problem is
diagnosed.
Both FQ exposure and the risk of subsequent devel
opment of tendon disorders, including rupture, have a
strong association.45 Other conditions that have been
implicated but not been well studied include increased age
(>60 years), concomitant use of corticosteroids, participa
tion in sports, and trauma, kidney disease, and rheumatoid
arthritis. As many as half of patients with FQ-associated
tendinopathy experience tendon rupture, and almost one-
third of patients have received long-term corticosteroids. 46
Tendon injury is mostly reported in the lower extremities,
with Achilles tendon being reported most frequently 46,47;
however multiple other tendons may be involved.45 Symp
toms of tendon injury are reported after a median of 8 days
of initiation of treatment, but they may appear as early as 2
hours after the first dose and as late as 6 months after treat
ment.46 Patients typically complain of pain after some days
of pharmacological treatment.
Clinical findings may include myalgia with or without
weakness, arthralgia, tendon swelling, warmth, and tender
ness.7,45 Hall et al45 described key management guidelines
for musculoskeletal complications as follows: ( a) identify
higher-risk individuals, ( b) avoid concomitant use of cor
ticosteroids, (c) limit high-intensity physical activity, ( d)
discontinue use of FQs if symptoms develop, (e) protect
the symptomatic area to limit further injury, and (f) initi
ate gradual return to physical activity. If signifi cant injury
is clinically suspected, referral for imaging modalities such
as magnetic resonance imaging and diagnostic ultrasonog
raphy can be helpful in evaluating the tendon and grading
severity. 45 Symptoms typically resolve after discontinuation
of the medication.
RETINOID-INDUCED MYOPATHY
Isotretinoin (Accutane) is an orally active synthetic retinoid
that has revolutionized the treatment of acne but has also
been
associated
with
muscular
adverse
effects.48
Musculoskeletal adverse effects such as myalgia, arthralgia,
arthritis, and rhabdomyolysis muscle damage are known
to occur; however, these are usually mild. 49 Creatine phos
phokinase, a specific marker of muscle destruction, has
been found to be elevated, occasionally by up to 100 times
the normal value (with or without muscular symptoms and
signs), in a variable percentage of patients receiving
isotretinoin treatment and particularly in those perform
ing vigorous physical exercise.49 In addition, intense physi
cal exercise and concurrent treatment with neurotoxic or
myotoxic drugs should be avoided during treatment with
oral retinoids.
ANTIRHEUMATIC AGENT-INDUCED
MYOPATHY
Gout is a common rheumatic condition with a varied clini
cal spectrum of diseases with hyperuricemia, recurrent
attacks of acute arthritis associated with urate crystals in
TABLE 6 Clinical Pearlsa
Differentiating a neuropathy from a myopathy during the
physical examination:
-  Although important exceptions exist, weakness that is
predominantly proximal is usually indicative of a myopathic
disorder and weakness that is predominantly distal indi
cates a neuropathic condition.
-  Segmental weakness involving selected myotomes in a
multifocal distribution may implicate a motor neuropathy
(disorder of the anterior horn cell).
-  Task-specifc fatigable weakness raises suspicion of a disor
der of neuromuscular transmission.
-  Results of sensory testing are commonly abnormal in
patients with neuropathies and normal in patients with
myopathic conditions.
-  Refexes are usually diminished or absent in generalized
neuropathies, sometimes out of proportion to the degree of
weakness. Alternatively, refexes are relatively preserved in
myopathies, unless the condition is quite advanced.
Identifcation of risk factors for development of a statin
associated myopathy:
-  Risk factors for the development of a statin-associated
myopathy include concurrent medications (eg, f brates
and calcium-channel blockers), older age, hypothyroidism,
hepatic dysfunction, and a high body mass index.
-  The risk of a statin-induced myopathy is dose-dependent,
and the risk among patients who receive high-dose therapy
is higher by a factor of 10 than the risk among patients who
receive more moderate doses; simvastatin may be particu
larly notorious in this regard.
Identifcation of risk factors for the development of critical
illness myopathy
-  Patients with prolonged stays in the intensive care unit are
at risk for developing critical illness myopathy, which typi
cally results in faccid quadriparesis and is accompanied by
polyneuropathy.
aBased on data from Fazio.56
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Page 6
the synovial fluid, deposits of urate crystals in tissues and
around joints, and renal complications.50 Clinical fi ndings
may be characteristic of multiple rheumatic disorders and
may include sudden severe attacks of pain, swelling, red
ness, and tenderness in the joints. Often, the great toe
(podagra) is involved but can occur anywhere in the feet,
ankles, wrists, fingers, and elbows. 51,52
Colchicine (Colcrys) is an antimitotic drug that is
highly effective in relieving acute attacks of gout if initi
ated within 24 hours.52,53 Although it is a highly effective
therapy, oral colchicine can cause dose-dependent gas
trointestinal adverse effects, including nausea, vomit
ing, and diarrhea. Other important nongastrointestinal
adverse effects include neutropenia and axonal neuromy
opathy, which may be worsened in patients taking other
myopathic drugs such as  -hydroxy- -methylglutaryl
coenzyme A reductase inhibitors (statins) or in those
with renal insuffi ciency. 54 After long-term use, colchicine
causes myopathy due to an accumulation of lysosomes
and autophagic vacuoles, as well as axonal neuropathy.
Symptoms of colchicine myopathy include proximal mus
cle weakness, elevation of serum CK level, distal sensory
involvement, and arefl exia. 9 Symptoms resolve within 4 to
6 weeks after discontinuation.
CONCLUSIONS
A number of medications prescribed are associated with
myotoxic side effects ranging from muscle weakness to
life-threatening muscle damage and subsequent renal fail
ure.55 Their safe use is dependent on appropriate drug
choice when initially prescribing and careful monitoring
thereafter, including identification of neuromuscular
adverse effects ( Table 6 ). Rehabilitation professionals can
assist in the management of patients who take medica
tions to ensure early identification of any new muscle com
plaints or changes in physical abilities. Knowledge of these
myopathies and patients at risk is important since timely
diagnosis assists in prompt management and full recovery.
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