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Drug-induced movement disorders

Stephen R Duma
John Morris movement SUMMARY
disorders fellow1
Clinical lecturer2 Many therapeutic and illicit drugs can cause movement disorders. Antipsychotics and antiemetics
Victor SC Fung are most commonly implicated.
Director1 The time of onset of the movement disorder may be acute, subacute, or chronic. The severity can
Clinical associate professor2 range from mild to severe and life-threatening.
1
Movement Disorders Unit, Early recognition of a drug-induced movement disorder is essential to allow for prompt
Department of Neurology, intervention. This includes stopping the offending drug, supportive care, and sometimes other
Westmead Hospital, Sydney
pharmacological treatment.
2
Sydney Medical School,
University of Sydney
Introduction Tremor
Keywords Both therapeutic and illicit drugs can cause Drug-induced tremor is typically postural or
dystonia, neuroleptic neurological adverse effects, including movement kinetic, or both. It is symmetrical and occurs
malignant syndrome,
disorders. The most common causes of drug-induced acutely following drug ingestion or dose escalation.
parkinsonism, serotonin
syndrome, tardive movement disorders are dopamine receptor blocking Exceptions include tremor secondary to valproate,
dyskinesia drugs, including antipsychotics and antiemetics which can appear at therapeutic or during stable
(Table 1). Drug-induced movement disorders can treatment, or, rarely, tardive tremor. Tremor can occur
range from tremors to life-threatening syndromes. secondary to many drugs, including SSRIs, lithium,
Aust Prescr 2019;42:56–61
They can be classified chronologically based on the tricyclic antidepressants, antiepileptics (particularly
https://doi.org/10.18773/
time of onset after drug ingestion, as acute, subacute valproate), bronchodilators, amiodarone and
austprescr.2019.014
or tardive. immunosuppressives. Another underlying aetiology,
such as Parkinson’s disease, essential tremor or
Acute disorders hyperthyroidism, needs to be excluded.
Acute drug-induced movement disorders occur within Management consists of altering the dose of, or if
minutes to days of drug ingestion. They include possible stopping, the offending drug, or switching
akathisia, tremor, neuroleptic malignant syndrome, to an alternative drug. Should the offending drug
serotonin syndrome, parkinsonism-hyperpyrexia need to be continued, discuss the risks of the adverse
disorder and acute dystonic reactions.1-4 effects versus the benefits of continuing to ensure
Akathisia the patient is informed. If the drug is continued, drugs
typically used for essential tremor (for example,
Akathisia is a common, but often under-recognised,
propranolol) can occasionally be beneficial.
drug-induced movement disorder that can occur as
an acute, subacute or tardive reaction. It is a sense of Serotonin syndrome
internal restlessness, irritability and tension without Serotonin syndrome occurs secondary to drugs
necessarily manifesting with physical signs, unlike that increase serotonin activity (Table 1). Like
restless legs syndrome which is typically more severe neuroleptic malignant syndrome, it can be life-
and worse at night. Akathisia has been reported threatening, but milder forms can occur. Clinical
with dopamine receptor blockers, selective serotonin characteristics include:
reuptake inhibitors (SSRIs), antiepileptic drugs, and
cocaine. It can occur either after starting a dopamine
•• altered mental status

receptor blocker, dose escalation, or when switching •• signs of central nervous system hyperexcitability
to an alternative drug. –– movement disorders, including myoclonus,
tremor, akathisia
Akathisia often improves following cessation of the
offending drug. Anticholinergics, beta blockers, –– hyperreflexia, clonus, spasticity or rigidity,
benzodiazepines, amantadine, mirtazapine and seizures
clonidine have also been used with varying efficacy •• autonomic instability, including mydriasis, fever
and with minimal evidence. and tachycardia.

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Table 1 Drug-induced movements disorders

Movement disorder Implicated drugs

Akathisia Dopamine receptor blocking drugs

Selective serotonin reuptake inhibitors
Antiepileptics

Tremor Selective serotonin reuptake inhibitors

Lithium
Tricyclic antidepressants
Antiepileptics (e.g. valproate)
Bronchodilators
Amiodarone
Immunosuppressive drugs (tacrolimus, ciclosporin)

Serotonin syndrome Selective serotonin reuptake inhibitors

(usually due to overdose Serotonin noradrenaline reuptake inhibitors
or combinations of Tricyclic antidepressants
serotoninergic drugs)
Monoamine oxidase inhibitors
Lithium
Linezolid
Opioids (pethidine, tramadol, propentadol)
Antiepileptics (valproate, lamotrigine)
St John’s wort

Acute dystonic reaction Dopamine receptor blocking drugs (e.g. antipsychotics, metoclopramide)
Selective serotonin reuptake inhibitors
Opioids
Methylphenidate
Rivastigmine
Albendazole
Gabapentin
Cetirizine
Foscarnet
Quinine
Propofol
Sevoflurane

Neuroleptic malignant Antipsychotics (e.g. haloperidol, fluphenazine, chlorpromazine)

syndrome Prochlorperazine
Metoclopramide
Droperidol
Promethazine
Tetrabenazine
Lithium

Parkinsonism Dopamine receptor blocking drugs (e.g. antipsychotics)

Calcium channel antagonists (e.g. flunarizine, cinnarizine)
Antiepileptics (e.g. phenytoin, valproate, levetiracetam)
Antidepressants (e.g. selective serotonin reuptake inhibitors, monoamine oxidase inhibitors)
Lithium
Chemotherapeutic drugs (e.g. cystosine arabinoside, cyclophosphamide, vincristine, adriamycin, doxorubicin, paclitaxel, etoposide)
Immunosuppressive drugs (e.g. ciclosporin, tacrolimus)
Toxins (e.g. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), organophosphate pesticides, manganese, methanol,
cyanide, carbon monoxide and carbon disulphide)

Tardive drug-induced Antipsychotics

movement disorders Antiemetics (e.g. metoclopramide)

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The altered mental status, autonomic instability, Management

and spasticity or rigidity with raised creatine kinase,
Stop the offending drug, and give an intravenous
overlap with neuroleptic malignant syndrome. In
or intramuscular anticholinergic drug (such as
serotonin syndrome the onset is hyperacute, within
benzatropine or trihexyphenidyl (benzhexol)
hours rather than days, and the signs of central
hydrochloride). As the injectable drug has a short
nervous system hyperexcitability are more prominent.
half-life it is followed by a short course of oral
Management anticholinergic drugs.4,5,7 Benzodiazepines have also
been used. It is important to avoid the offending
Discontinuation of the offending drugs and
drug in the future due to the risk of a recurrent
supportive care (which may include intensive
dystonic reaction. Educate the patient regarding
care) are first-line in treating serotonin syndrome.
this risk.
Cyproheptadine may be given in less severe cases
and, if a response is observed, it should be continued Neuroleptic malignant syndrome
until symptoms resolve.5 Benzodiazepines or other
Neuroleptic malignant syndrome is a potentially
5-hydroxytryptamine 2 receptor antagonists (such
life-threatening reaction to typical and atypical
as chlorpromazine or olanzapine) have been used in
antipsychotic drugs and other dopamine receptor
severe cases.4,5
blocking drugs, including tetrabenazine, lithium
Parkinsonism-hyperpyrexia disorder and antiemetics such as metoclopramide. Delphi
consensus diagnostic criteria8 have been recently
Parkinsonism-hyperpyrexia disorder, also known
validated.9 These criteria include:
as akinetic crisis, is a rare but potentially fatal
complication of Parkinson’s disease. It involves a •• exposure to a dopamine antagonist, or dopamine
syndrome of significantly worsening parkinsonism agonist withdrawal, within the past 72 hours
(with or without encephalopathy), hyperpyrexia, •• hyperthermia (>38 °C on at least two occasions)
autonomic instability and elevated creatine
•• rigidity
kinase.4-6 The disorder is most commonly seen
in patients with Parkinson’s disease who have •• altered mental status

reduced or stopped their antiparkinsonian drugs. •• elevated creatine kinase

It can also be precipitated by an infection or other •• autonomic instability (including hypermetabolism,
metabolic disturbance. The clinical features overlap i.e. tachycardia and tachypnoea)
with neuroleptic malignant syndrome. It is also •• negative investigations for an alternative cause.
important to exclude alternative causes, including
In addition to the elevated creatine kinase, laboratory
an underlying infection, metabolic abnormalities,
investigations usually find leucocytosis, abnormal
or stroke. Recovery can take hours to weeks
electrolytes, renal impairment, abnormal liver function
following treatment.
tests, and altered coagulation studies. Milder cases
Management without all the clinical features can occur.
The mainstay of treatment includes resuming anti- There are a number of differential diagnoses,
parkinsonian drugs, usually via nasogastric tube including serotonin syndrome, and specialist
because of the dysphagia resulting from severe assessment is required. For example, serotonin
parkinsonism. Intermittent apomorphine injections or syndrome tends to occur more acutely than
a continuous infusion may be required in moderate– neuroleptic malignant syndrome. There is rigidity in
severe cases. neuroleptic malignant syndrome whereas myoclonus,
hyperreflexia with clonus, and mydriasis are more
Acute dystonic reactions common in serotonin syndrome.
Acute dystonic reactions most commonly occur in
younger patients soon after taking to dopamine Management
receptor blocking drugs, including antiemetics If neuroleptic malignant syndrome is suspected,
(e.g. metoclopramide or prochlorperazine) and acute hospital admission is warranted. Management
antipsychotics. Acute sustained dystonic spasm of involves immediate cessation of the offending drugs,
craniocervical muscles is typical, but oculogyric crises, supportive care (which includes intensive care if
truncal spasm causing opisthotonos, or limb dystonia severe), and giving a dopaminergic drug, usually
can also occur. Acute laryngeal dystonia can be life- bromocriptine. Subcutaneous apomorphine injections
threatening due to airway obstruction and requires have also been used. Benzodiazepines can be used to
emergency medical care. reduce rhabdomyolysis and improve rigidity.

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The syndrome typically plateaus and improves not be required. Amantadine can also be used to
within 2–3 weeks of onset. Bromocriptine should manage levodopa-induced dyskinesias. Referral is
therefore be continued for several weeks to ensure recommended for patients with late-stage disease for
the syndrome has completely subsided. Consideration consideration of device-assisted therapy.
about restarting an antipsychotic requires a specialist
Tardive disorders
psychiatric opinion.
Tardive drug-induced movement disorders occur
Subacute disorders either during exposure or within weeks of stopping
Subacute drug-induced movement disorders occur a drug and are present for at least one month.1,11-14
within days to weeks of drug ingestion. Some The minimum duration of exposure to the drug is
of the syndromes listed in Table 1 can develop three months, or one month in adults aged over
subacutely. They usually respond to cessation of the 60 years. The most commonly implicated drugs
offending drug. include antipsychotics, antiemetics (metoclopramide
and prochlorperazine) and some calcium channel
Parkinsonism antagonists with dopamine receptor blocking
Drug-induced parkinsonism is typically characterised properties (cinnarizine and flunarizine).
by bradykinesia, rigidity and postural instability. It is
Tardive movement disorders include dyskinesias
the second commonest cause of parkinsonism after
(typically orobuccolingual), stereotypies, akathisia,
idiopathic Parkinson’s disease. Various drugs have
dystonia (focal, segmental or generalised), myoclonus,
been associated with parkinsonism (see Table 1).
tremor and tics. Additionally, tardive parkinsonism
In contrast to idiopathic Parkinson’s disease, may be experienced. Withdrawal-emergent
drug-induced parkinsonism usually presents as a dyskinesia can occur on abrupt cessation of long-term
symmetrical akinetic rigid syndrome which develops antipsychotic treatment, particularly in children. The
over days to weeks to months following ingestion dyskinesia improves on resuming the drug. The dose
of the offending drug. Additionally, there is a poor can then be gradually reduced.
response to typical antiparkinsonian drugs, including
levodopa, dopamine agonists and anticholinergic Management
drugs. Cessation of the offending drug usually results No good evidence exists regarding the management
in complete resolution of the disorder. of tardive drug-induced movement disorders.15
Additionally, toxins can cause parkinsonism. These Treatment usually consists of withdrawing the
include 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine offending drug, and a trial of a combination of drugs.
(MPTP), organophosphate pesticides, manganese, Clonazepam has been effective particularly for
methanol, cyanide, carbon monoxide, and carbon myoclonus. Resuming the offending drug or changing
disulphide. Unlike the drugs, toxins are often to an atypical antipsychotic is sometimes required.16
In patients with a chronic psychotic disorder clozapine
associated with irreversible structural damage to the
is preferred. Most recently, vesicular monoamine
basal ganglia visible on MRI.
transporter 2 inhibitors deutetrabenazine and
Levodopa-induced dyskinesia valbenazine have been proposed as treatment
Levodopa-induced dyskinesia is a common cause of options.17,18 Other oral drugs have been tried, including
dyskinesia in individuals with Parkinson’s disease. It tetrabenazine, amantadine and propranolol.
occurs due to the relationship between dopaminergic Antioxidants, including vitamin E, vitamin B6 and
loss and the resultant response to levodopa, rather Ginkgo biloba, have also been studied. Vitamin E had
than being due to excess levodopa ingestion only. conflicting results, while vitamin B6 and Ginkgo biloba
Risk factors for developing dyskinesia include young are probably useful in treating tardive movement
age at onset of Parkinson’s disease, higher levodopa disorders.17,18 Caution is needed with Ginkgo biloba
dose, low body weight, and more severe disease.10 because of its antiplatelet effects, especially in
A careful history is vital in establishing a pattern to patients taking antiplatelet drugs or anticoagulants.
the timing and duration of dyskinesias, which can then Anticholinergic drugs to prevent, or reduce the
assist in altering the levodopa dose. severity of, drug-induced movement disorders have
Depending on the duration of dyskinesia, the been suggested, however there is no evidence to
levodopa dose can usually be reduced to a lower support this.
dose which still maintains efficacy. It is worth noting Botulinum toxin injections can be effective for focal
that mild dyskinesias are often not bothersome manifestations of tardive dystonia.19 Deep brain
to the individual and do not interfere with their stimulation, targeting the globus pallidus, can be
function, therefore a change in levodopa dose may highly effective in severe cases.20

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 VOLUME 42 : NUMBER 2 : APRIL 2019

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Illicit drugs most commonly dopamine receptor blocking

Movement disorders secondary to illicit drugs are drugs. Patients are often on combinations of
usually acute and self-limiting,4,21 but can occasionally drugs that may cause more than one movement
SELF-TEST be life-threatening (Table 2). Cocaine blocks disorder, thereby making it challenging to
QUESTIONS dopamine reuptake thereby increasing dopaminergic identify the culprit drug. The diagnosis requires
True or false? drive. Amphetamines cause more widespread knowledge of the typical movement disorders
catecholaminergic stimulation, but chronic use results and the syndromes that can occur with different
1. Antiemetics can
cause neuroleptic in dopamine depletion, and is possibly associated with drug classes, and their typical time course.
malignant syndrome. This is important because the most imperative
nigral damage.22 3,4-methylenedioxymethamphetamine
2. Levodopa should therapeutic intervention for most drug-induced
be stopped if a patient (MDMA) is known to cause parkinsonism and a
syndrome similar to serotonin syndrome. movement disorders is stopping the offending
with Parkinson’s disease
develops parkinsonism- drug, with or without supportive or other
While the movement disorder usually occurs
hyperpyrexia disorder. pharmacological treatment.
following drug ingestion, it can also occur during the
Answers on page 79 Victor Fung receives a salary from NSW Health, has
withdrawal phase. Typically, it subsides on cessation of
the drug, but can last for months. No specific treatment received unrestricted research grants from Abbvie and
exists for movement disorders caused by illicit drug use. Merz, is on advisory boards and has received travel
grants from Abbvie, Allergan, Cavion, Ipsen, Merz,
Praxis, Seqirus, Stada, Teva and UCB, and receives
Conclusion
royalties from Health Press.

Movement disorders are a common, and at times Dr Duma has received a speaker honorarium
life-threatening, adverse effect of many drugs, from UCB.

Table 2 Illicit drugs and associated movement disorders

Drug Movement disorder

Cocaine Choreoathetosis (chorea and dystonia, also known as ‘crack dancing’)

Stereotypies
Tremor
Myoclonus

Amphetamines Punding (purposeless, repetitive behaviours)

Tremor
Dystonia
Choreoathetosis
Orolingual dyskinesia

3,4-methylenedioxymethamphetamine (MDMA) Serotonin syndrome

Parkinsonism

Opioids Myoclonus

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FURTHER READING
Jamshidi N, Dawson A. The hot patient: acute drug-induced
hyperthermia. Aust Prescr 2019;42:24-8. https://doi.org/
10.18773/austprescr.2019.006

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