Neuropsychiatric side-effects of lidocaine: examples from the treatment of headache and a review.

Abstract

Lidocaine has been used in treatment of patients with refractory headache. Personal observations of neuropsychiatric toxicity in these patients led us to review our cases and the literature systematically for lidocaine side-effects, especially neuropsychiatric symptoms. In our series of 20 patients, side-effects were observed in all, the most frequent being neuropsychiatric (75%) and cardiological (50%). When reviewing published series on intravenous lidocaine use, reports of side-effects range from 0 to 100%, with neuropsychiatric symptoms being reported in 1.8-100%. Thirty-six case reports of lidocaine-induced psychiatric symptoms were also analysed. Psychiatric symptoms of toxicity were similar in most patients, despite their differing ages, pathologies, co-therapies and lidocaine dosages. In conclusion, lidocaine neuropsychiatric toxicity has a well-recognized stereotypical clinical presentation that is probably unrecognized in headache series. As lidocaine represents an emerging alternative therapy in headache, particularly in short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, clinicians and patients should be aware of the extent of this problem.

Full text

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Neuropsychiatric side-effects of lidocaine: examples from the
treatment of headache and a review
R Gil-Gouveia & PJ Goadsby
Headache Group-Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
Gil-Gouveia R & Goadsby PJ. Neuropsychiatric side-effects of lidocaine:
examples from the treatment of headache and a review. Cephalalgia 2009;
29:496–508. London. ISSN 0333-1024
Lidocaine has been used in treatment of patients with refractory headache.
Personal observations of neuropsychiatric toxicity in these patients led us to
review our cases and the literature systematically for lidocaine side-effects,
especially neuropsychiatric symptoms. In our series of 20 patients, side-effects
were observed in all, the most frequent being neuropsychiatric (75%) and
cardiological (50%). When reviewing published series on intravenous lidocaine
use, reports of side-effects range from 0 to 100%, with neuropsychiatric symp-
toms being reported in 1.8–100%. Thirty-six case reports of lidocaine-induced
psychiatric symptoms were also analysed. Psychiatric symptoms of toxicity were
similar in most patients, despite their differing ages, pathologies, co-therapies
and lidocaine dosages. In conclusion, lidocaine neuropsychiatric toxicity has a
well-recognized stereotypical clinical presentation that is probably unrecognized
in headache series. As lidocaine represents an emerging alternative therapy in
headache, particularly in short-lasting unilateral neuralgiform headache attacks
with conjunctival injection and tearing, clinicians and patients should be aware
of the extent of this problem. ?Lidocaine, headache, toxicity, psychiatric reaction
Professor Peter J. Goadsby, UCSF Headache Center, 1635 Divisadero St,
San Francisco, CA 94115, USA. Fax + 1 415 353 9383, e-mail
pgoadsby@headache.ucsf.edu Received 13 October 2004, accepted 30 December 2004
Introduction
Lidocaine has been used as a local anaesthetic since
1943 and as an anti-arrhythmic drug since 1950 (1).
It has been used systemically in chronic and acute
pain states since 1961 (2) and in headache patients
since 1984 (3). Lidocaine can be a useful adjunct in
some patients with headache, with the most sub-
stantial concern for neurologists and headache spe-
cialists being that of cardiac side-effects.
Lidocaine is metabolized by the microsomal
enzyme system in the liver and excreted in the
urine;after intravenous
lidocaine plasma concentration describes a biphasic
curve, with an early rapid fall around 8–17 min and
a second slow decrease around 87–108 min (1).
Lidocaine exerts its action through sodium channel
blockade and subsequent suppression of cellular
excitability (4). The effect of lidocaine in headache
(i.v.) administration
may be mediated by central neural inhibition at the
level of the spinal trigeminal nucleus (5). Although
generally regarded as a safe drug, side-effects to
lidocaine have long been recognized (6, 7). The
most frequent type of adverse reaction described is
generally dose dependent and due to central
nervous system involvement, and includes perioral
numbness, drowsiness, visual disturbances, sweat-
ing, weakness, heavy respirations, muscle twitch-
ing, euphoria, agitation, difficulty in concentrating
and speaking, dysarthria, diplopia, psychotic reac-
tions, shaking and eventually generalized convul-
sions or coma (8, 9). These events seem to occur in
a crescendo sequence but usually resolve quickly
after stopping the infusion, as long as hepatic and
cardiac function are normal (1, 8, 10).
Prompted by an observation of neuropsychiatric
side-effects in patients we treated with i.v. lidocaine
for headache, we systematically reviewed our cases.
doi:10.1111/j.1468-2982.2008.01800.x
496 © Blackwell Publishing Ltd Cephalalgia, 2009, 29, 496–508

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We also performed a literature review on i.v.
lidocaine-induced toxicity. Our purpose was to
evaluate lidocaine toxicity and its side-effect profile,
with special reference to neuropsychiatric symp-
toms, in order to highlight the problem for the
headache community.
Methods
Review of cases
We reviewed charts for all headache in-patients
treated with i.v. lidocaine (lignocaine) at the
National Hospital of Neurology and Neurosurgery
in 2002, 2003 and up to May 2004 as part of a
clinical audit of our in-patient care. The headache
diagnosis of each patient was made prior to the
infusion. The decision to use i.v. lidocaine was
made by the clinician in charge of the case usually
faced with syndromes intractable to routine medical
therapy. Patients were not considered for treatment
if they had a previous history of allergic reactions to
local anaesthetics, cardiac arrhythmias or if they
were pregnant or breast-feeding.
All patients had pretreatment cardiological evalu-
ation, 12-lead electrocardiogram and routine bio-
chemical tests with liver enzyme level estimations.
Cardiac monitoring and fluid chart balance were
maintained during the course of the infusion. The
treatment consisted of a constant infusion of a 0.4%
lidocaine solution—2 g lidocaine diluted in 500 ml
glucose 5%—that was started at 1 mg/min (11).
Dose escalation was determined individually and
was typically performed at 1 mg/min increases
every 24 h, moving to a maximum dose of 4 mg/
min (approximately 3.4 mg kg-1h-1), if required. At
the start and at each dose escalation, pulse rate and
blood pressure were measured every 5 min for the
first 30 min, every 15 min for the next 4 h and four
hourly thereafter. Hourly headache pain charts
recording the pain level on a verbal rating scale of
1–10, or tabulation of attacks for short-lasting head-
aches, was performed throughout treatment. Levels
of lidocaine in the blood were not determined.
Demographic and clinical data were tabulated as
were treatment response and adverse events. The
later were classified into four major groups includ-
ing cardiovascular, neuropsychiatric, gastrointesti-
nal and other symptoms. Neuropsychiatric events
were further classified into neurological or psychi-
atric, or both, according to their main characteris-
tics. A full description of the clinical features is
included in the Results section.
Statistical analysis was performed using logistic
regression to look for a predictor of psychiatric
adverse events (SPSS v 11.5; SPSS Inc., Chicago, IL,
USA). Treating the presence of psychiatric adverse
events as a binary (present or absent) and regress-
ing against headache type, days of treatment, pres-
enceofa psychiatric
significance was assessed at P < 0.05 with the
Hosmer–Lemeshow goodness-of-fit statistic (12).
history,age andsex,
Literature review
We performed a MEDLINE search in order to iden-
tify case series regarding the clinical use of i.v.
lidocaine in adults and case reports on lidocaine
toxicity, with special interest in psychiatric effects.
Keywords used included i.v. lidocaine, lignocaine,
toxicity, neurological, neuropsychiatric and psychi-
atric. No time restrictions were applied. Papers
related to non-intravenous lidocaine use were
excluded. Relevant references were also sought by
hand searching headache journals.
Results
Review of cases
Patients
In total 20 patients had i.v. lidocaine in the period
reviewed. Twelve patients were female (60%), with
an average age for all patients of 44 years (range
19–65 years). Eleven of 20 patients (55%) had short-
lasting unilateral neuralgiform headache attacks
with conjunctival injection and tearing (SUNCT)/
short-lastingunilateral
attacks with cranial autonomic symptoms (SUNA)
syndromes (13), four had migraine (two chronic
migraine and two chronic migraine with medica-
tion overuse)and five
types. The latter included chronic post-traumatic
headache, glossopharyngeal neuralgia, idiopathic
stabbing headache, trigeminal dysaesthesia and
pituitary tumour-associated headache (Table 1).
neuralgiformheadache
had other headache
Investigations
Patient electrocardiograms demonstrated normal
sinus rhythm and no significant conduction abnor-
malities. Blood tests were within normal ranges
with the exception of five patients who presented
with borderline elevations of serum potassium
(n = 1), alanine transaminase (n = 3) and alkaline
phosphatase (n = 1).
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Table 1 Patient characteristics and lidocaine side-effects
Sex
Age
Headache
diagnosis
Headache
prophylaxis
(daily dosage)
Headache
relief
Infusion
duration
(days)
Infusion rate
(mg/min)
Previous
psychiatric
history
Side-effects
Maximum
Toxic
Cardiovascular
Psychiatric
Neurological
Gastrointestinal
Other
F
61
SUNCT
GBP (1600 mg)
+
7
3.7
3.7
+
+
+ S*
+
-
-
F
30
SUNCT
GBP (2400 mg)
-
2
2
No
-
+
-
+
-
-
DPH (300 mg)
TAD (150 mg)
M
52
SUNCT
GBP (2700 mg)
+
7
4
4
-
+
-
+
+
-
M
49
SUNCT
bB (160 mg)
+
5
3
2
-
-
+ S*
-
+
-
F
36
SUNCT
CBZ (800 mg)
+
5
4
4
+
-
+ S*
-
-
+
F
54
SUNCT
LTG (400 mg)
+
7 / 5
3
2.7
-
+
+ S*
+
+
-
TPM (100 mg)
M
59
SUNCT
GBP (2400 mg)
+
6
4
4
+
+ S*
-
-
-
-
CBZ (200 mg)
bB (25 mg)
F
51
SUNCT
-
+
4
2
2
-
+
-
-
-
-
M
65
SUNCT
CBZ (800 mg)
+
4
3
3
-
-
+ S*
-
-
-
M
50
SUNCT
GBP (3600 mg)
+
7
4
3
-
+
+
+
-
+
LTG (600 mg)
TAD (50 mg)
M
34
SUNCT/ SUNA
-
+
7
3
3
-
-
+
-
+
-
F
28
Pituitary headache
-
+
9
3
3
+
-
-
+ S*
-
-
F
62
Trigeminal
dysaesthesia
TAD (30 mg)
-
7
3
3
-
+
-
-
-
+
F
28
Status migrainosis
VPA (400 mg)
+
7
3
2
-
-
-
+
+
-
M
35
Post-traumatic
headache
TPM (100 mg)
+
8
4
3
+
-
-
+
-
-
F
46
Chronic migraine
with analgesic
overuse
TAD (125 mg)
+
6
4
No
+
+
-
-
-
-
F
49
Chronic migraine
-
+
10
3
2
-
-
+
+
+
-
F
54
Hemiplegic migraine
with analgesic
overuse
-
-
5
4
4
-
-
+ S*
+
-
+
F
25
Glossopharyngeal
neuralgia
-
+
6
4
3
-
-
-
-
+
-
M
19
Idiopathic stabbing
headache
TPM (250 mg)
+
6
3
++
+
+ S*
-
-
+
+, yes; -, no; S*, infusion stopped for side-effects; GBP, gabapentin; CBZ, carbamazepine; TPM, topiramate; LTG, lamotrigine; DPH, phenytoin; VPA, sodium valproate; TAD, tricyclic
antidepressants; bB, b-blockers.
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Previous treatments for headache
All patients included in the lidocaine protocol were
highly refractory to previous treatments. The mean
number of preventive treatments that were previ-
ously unsuccessful was 10, ranging from three to
20. The most frequent previously used drugs were
amitriptyline (18/20), gabapentin (15/20), carbam-
azepine and topiramate (13/20), sodium valproate
(12/20), indomethacin (12/20), lamotrigine and cor-
ticosteroids (10/20). Other drugs frequently used
included verapamil, pizotifen, propranolol, methy-
sergide and morphine. The range of medicines pre-
viously used relates to the fact that many patients
had been referred from other clinicians and does
not represent simply the range of medicines used
by us.
Known comorbid illnesses
All patients had some, usually minor, previous
comorbidity. This included hypercholesterolaemia
(n = 5), mild asthma (n = 4), rheumatoid arthritis
and irritable bowel disease (n = 3 each), high blood
pressure, hypothyroidism, peptic ulcer disease and
obesity (n = 2 each). Four patients were current mild
smokers and four were ex-smokers. There was a
previous history of depression in seven patients,
one of whom had obsessive symptoms. Two
patients had had previous neoplastic diseases—
cerebral astrocytoma in one, and breast and cervix
carcinomas in another. Other important comorbidi-
ties included severe active Crohn’s disease, active
ischaemicoptic neuropathy,
adenoma, brainstem lesion of unknown aetiology,
left middle cerebral artery territory minor stroke
and previous chemical meningitis, reported in one
patient each. Three patients had a previous history
compatible with cranial nerve pathology, including
one patient who had Bell’s palsy at age 12 years.
benign pituitary
Headache response to i.v. lidocaine
Most patients responded favourably to lidocaine,
with 17/20 reporting improvement or complete
relief of previous headaches (Table 1). The average
number of days of treatment was six, ranging from
2 to 10 days. Rescue treatments for headache and
nausea used during the infusion included: chlor-
promazine (n = 4), granisetron (n = 7), domperidone
(n = 7), naproxen (n = 3) and i.v. aspirin (n = 3).
Medications concurrent with lidocaine infusion
During the course of the lidocaine infusion, patients
continued their previous prophylactic headache
medication as well as other chronic medication that
they might have been on. Headache prophylactics
included: gabapentin (n = 5), carbamazepine (n = 3),
topiramate (n = 3), lamotrigine (n = 2), phenytoin
(n = 1), sodium valproate (n = 1), tricyclic antide-
pressants (n = 4) and b-blockers (n = 2). Other
chronic medication included selective serotonin
re-uptake inhibitors (n = 2), benzodiazepines (n = 3)
and zolpidem (n = 2), daily aspirin for secondary
stroke prophylaxis (n = 2), statins (n = 3), proton
pump inhibitors (n = 3), levothyroxine (n = 3) and
hormonal treatments(n = 3).
included methotrexate, vitamin supplements, anti-
asthma inhalators and antispasmodics or other
drugs altering gut motility.
Patients less likely to benefit from lidocaine infu-
sion were on prophylaxis with tricyclic antidepres-
sants (c24.804, P = 0.028). Phenytoin prophylaxis
was also related to lower benefit from lidocaine (c2
5.965, P = 0.015), although this relates to one patient
only, who was also on tricyclic antidepressants
(Table 1). Other preventives did not influence the
therapeutic response to lidocaine.
Other treatments
Adverse events on lidocaine
All patients suffered some type of adverse event,
but none wasconsidered
threatening. The mean number of adverse events
per patient was two, ranging from one to four. In
seven out of 20 cases the symptoms led only to
transitory infusion suspension, restarting after a
short break at the same rate, whereas in four there
was a permanent reduction of the infusion rate.
Nine of 20 patients had their treatments eventually
stopped due to side-effects, seven of which were
psychiatric, one neurological and one a cardiac
arrhythmia.
Patients on prophylactic headache therapy had
no increased incidence of any type of adverse event
(cardiovascular c23.810, P = 0.051; psychiatric c2
0.000, P = 1.000; neurological c20.000, P = 1.000; gas-
trointestinal c20.848, P = 0.357; and other c20.317,
P = 0.573). When analysing each preventive in
isolation, two medications were related to the
occurrence of cardiovascular events—gabapentin
(c26.667, P = 0.01) and tricyclic antidepressants (c2
5.000, P = 0.025), although again the numbers were
small. No other agent influenced any other type of
event, not even b-blockers. Analysis was also per-
formed grouping preventives into antiepileptics in
general, enzymatic inductor antiepileptics and anti-
epileptics with action on sodium channels. Still, we
found no evidence of influence of these medications
on the occurrence of adverse events.
serious orlife-
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Cardiovascular adverse events
Cardiovascular adverse events were reported in 10
of 20 cases. Nine were mild and included two cases
of high blood pressure, two of low blood pressure,
four of tachycardia and one of bradycardia. Only
three of these patients had their infusion rate
reduced or stopped for a period of time (2–15 h).
One case had an episode of self-limited atrial fibril-
lation and the infusion was stopped.
Psychiatric adverse events
Psychiatric symptoms were present in 10/20 (50%)
patients, and included dysphoria (n = 2), depressive
mood (n = 2), depressive mood with paranoid ide-
ation (n = 2) and agitation with visual and auditory
hallucinations (n = 5). One patient with SUNCT
with marked paranoid ideation had such an excel-
lent clinical response that she requested the infu-
sion be repeated 1 year later. She had a further
almost identical episode of paranoid thinking and
behaviour, which was foreshortened as we had
suspected it might occur and the infusion was
quickly stopped. All but two of these patients had
their infusion stopped on account of psychiatric
symptoms, whereas the others tolerated the effects
and continued for the therapeutic trial.
The occurrence of psychiatric adverse events was
not related to any of the variables in the model. The
Hosmer and Lemeshow test was not significant
(c28= 9.51, P = 0.33). Wald tests for each of sex
(P = 0.36), age (P = 0.36), type of headache (P = 0.18),
length of treatment (P = 0.9), previous history of
depression or psychiatric illness (P = 0.64) and
occurrence of other type of side-effect (P = 0.31)
were negative.
Neurological adverse events
Neurological symptoms were frequent (10/20, 50%)
and included dizziness, light headiness or drowsi-
ness (n = 5), perioral or limb paraesthesia (n = 4),
visual disturbances, blurred vision and transitory
double vision (n = 2), confusion, disorientation and
cognitive difficulties (n = 1) and frequent visual and
sensitive auras (n = 1 each). One patient had the
infusion stopped for neurological symptoms, two
had permanent reduction of the infusion rates and
one had transient infusion suspension for 8 h for
blurred vision.
Takentogether, neuropsychiatric
occurred in 15 of 20 (75%) patients that we treated.
symptoms
Gastrointestinal adverse events
The principal
registered was nausea (n = 6), and two patients
gastrointestinaladverse event
complained of constipation. Two patients had tran-
sient infusion suspension for nausea.
Other adverse events
Other symptoms reported included feeling hot in
the body (n = 3) and tiredness (n = 1), and another
patient had a minor local infusion site reaction due
to extravasation and subcutaneous infiltration of
lidocaine. Two patients who complained of feeling
hot had the infusion suspended for 30 min and then
re-started at the same rate, uneventfully.
Review of literature
Results from the literature review on unwanted
effects of i.v. lidocaine treatment in adults are pre-
sented in Table 2, including only case series (9, 10,
14–63). It includes 50 series and around 6000 patients
treated for different reasons: surgical patients (for
anaesthesia), pain and headache patients (for anal-
gesia), cardiac patients (for ventricular arrhythmias),
epileptic patients (for seizure control) and also
healthy volunteers in experimental conditions. The
side-effects rate varies in the different series, ranging
from 0 (27, 44, 45, 49, 50, 60) to 100% (16, 18, 21).
Major or life-threatening side-effects are infrequent,
most series reporting rates between 0.3% and 33.3%
for seizures, coma, severe heart block and cardiovas-
cular arrest (16, 28, 37). Psychiatric side-effects are
reported in 1.8–100% (17, 27).
Table 3 describes case reports on psychiatric
effects of lidocaine, independently of route of
administration (6, 8, 64–71, 73–78). It includes 17
reports involving 36 patients, mostly male (69%)
adults with cardiac disorders (78%). Most of these
toxicityreportsinvolve
lidocaine (8, 65–69, 73–75), but some are due to
subcutaneous (6, 64, 76–78) or oral (accidental) (71)
administration. Twenty patients (56%) had concur-
rent conditions or administration of other drugs
that could influence lidocaine toxicity. The psychi-
atric symptoms include excitement, euphoria and
agitation, sometimes evolving to doom anxiety,
delirium and frank psychosis with hallucinations.
i.v. administrationof
Discussion
Use of i.v. lidocaine to treat intractable headache
produced psychiatric side-effects in 50% of our
patients. Although recognized in the literature, the
incidence seems high and not widely discussed in
the neurological or headache community, in con-
trast to neurological side-effects that were as
common and more widely recognized. Our series
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Table 2 Case series involving i.v. lidocaine treatment
Source
Patients
Side-effects (maximum % reported)
Pathology
Lidocaine i.v.
administration
N*
Cardiovascular
Psychiatric
Neurological
Gastro-
intestinal
Other
(14)
SURGICAL PATIENTS
Anaesthesia with succinyldicholine+lidocaine;
1757
↓ BP
-
Sleepiness, drowsiness, seizures (0.3%)
Nausea
Warmth
(15)
Various major and
minor short-term
surgical procedures;
patients with postoperative pain
Intermittent dosage (0–750 mg); 800 mg/2 days,
or placebo or
Vomits
(16.5%)
(16)
500 mg i.m. + 1000 mg i.v.
(17)
HEALTHY
VOLUNTEERS (14
with experimental
pain)
0.5 mg/kg infusion; 250 mg at 20 mg/min;
50 mg bolus + rapid infusion; 15, 30 and
60 mg kg-1min-1
45
HR† ↑ (80%) or
↓ (10%); BP‡
↑ (90%)
Euphoria
(100%)
Twitching (100%), blurry vision, colour
blindness, lightheadedness (50%),
drowsiness, sleepiness, disorientation
(100%), numbness (60%), slurred
speech (85%), dysarthria (40%),
tinnitus (30%), ↑hearing (64.3%),
nystagmus (20%), seizures (8.3%)
-
RR§ ↑ (30%) or
↓ (40%)
(18) (19)(20)(21)
CARDIAC
ARRHYTHMIAS
1–2 mg bolus; 1.5 mg/kg bolus ? infusion
0.03–0.05 mg kg-1min-1; 1–2 mg/kg bolus ?
infusion 150 mg/h for 48 h;
1 mg/kg + 0.5 mg/kg bolus + infusion
2.8 mg/min for 48 h
153
Heart block
(2.5%)
Restlessness
(11.1%),
euphoria
(2.3%)
Lightheadness, sleepiness (100%),
drowsiness (27.3%), disorientation
(22.2%), confusion (7.5%), blurred
vision (7.5%), paraesthesias (6.8%),
twitching (22.2%), tremor (10 %),
seizures (22.2%)
Nausea
(10%)
-
(22)(23)
Various types of acute
and chronic
ventricular
arrhythmias
(24)(25)
CARDIAC
ARRHYTHMIAS
100 + 50 mg bolus + infusion 2.08 to
4.16 mg/min (? 50 mg bolus); 100 mg
bolus + infusion 60 mg/15 min + infusion
1.4 mg/min for 24 h
58
↓ BP/HR
(4.1%), ↑
VPC¶ (2%)
-
Drowsiness, sedation, stupor and
dysarthria (4.1%)
Nausea
(2%)
Diaphoresis
(11.1%)
(26)
Ventricular arrhythmias
after cardiac surgery
(10)
CARDIAC
ARRHYTHMIAS
25–100 mg bolus + infusion 0.5–10 mg/min;
25–100 mg multiple bolus
1034
Heart block
(7.7%), ↓ HR
/BP (12.5%),↑
BP (23.6%),
cardiac arrest
(1.4%)
Euphoria
(1.8%),
confusion,
agitation
(9.7%),
psychosis
Dizziness (9.5%), tinnitus (4.8%),
drowsiness (32.7%) sleepiness,
confusion and disorientation (25%),
dysarthria, numbness (62.5%), tremor,
vertigo, visual disturbances, ↓
hearing (1.8%), conscience loss
(12.5%), stupor (11.5%), coma (5.5%),
coma + respiratory depression (0.8%),
twitching (25%), focal seizures (7.7%),
generalized seizures (33.3%)
Nausea
Rash, phlebitis
(0.4%),
syncope,
apnoea (1.4%)
(27)(28) (29)
Ventricular
arrhythmias + ischaemic
heart disease; (750 hospitalized old
patients, age average
65 years and 27
cocaine-induced acute
myocardial infarction)
1–2 mg/kg bolus ? infusion 1–2 mg/min;
1–3 mg/kg single or multiple bolus; infusion0.015–0.045 mg kg-1min-1up to 5 days; 50 mg
? 100 mg bolus ? infusion 1 mg/min for
24 h; ?bolus + infusion
(30) (31) (32)
15–55 mg kg-1min-1
(33) (34)
ISCHAEMIC HEART
DISEASE
25–150 mg bolus ? infusion 1–4 mg/min;
25–150 mg bolus ? infusion 0.5–4 mg/min;
75 mg/2 min bolus + infusion 2 mg/min for
24 h {or placebo}; 75 mg bolus + infusion
2 mg/min for 30 h; 75 mg + 50 mg multiple
bolus up to 225 mg + infusion 1–4 mg/min;
75 mg bolus + infusion 8.33 mg/min for
18 min OR 50 mg multiple bolus; 300 mg
i.m. + 100 mg bolus {or placebo}; 100 mg
bolus + infusion 3 mg/min (? 100 mg bolus)
{or placebo}; 100 mg bolus + 300 mg i.m. {or
placebo}
2668
↑ PR interval
(4.4%), heart
Block, ↓ BP/
HR (2.9%)
cardiac arrest
(4%)
Psychotic
reaction with
anxiety and
confusion
(2.9%),
psychosis
(40%)
Drowsiness (8.3%), sleepiness (11%),
tinnitus (100%), dizziness (20%),
lightheadedness, confusion,
disorientation (< 5%), numbness
(5.9%), slurring of speech (11.1%),
dysarthria, double vision, changes in
hearing, tremor, twitching (< 5%),
coma (0.7%), seizures (2%)
Nausea
(11%)
Difficulty
breathing
(1.5%), ↓ RR,
Respiratory
arrest (0.7%)
(35)(36) (37) (38)(39)(40) (41)
Coronary ischaemic
disease or acute
myocardial infarction
(18 with heart failure)
(42) (43)
Lidocaine and headache
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Table 2 (Continued)
Source
Patients
Side-effects (maximum % reported)
Pathology
Lidocaine i.v.
administration
N*
Cardiovascular
Psychiatric
Neurological
Gastro-
intestinal
Other
(44)
BRONCHOSCOPY
1.5 mg/kg bolus {or placebo}
11
-
-
-
-
-
under general
anaesthesia
(45)
EPILEPSY and STATUS
EPILEPTICUS
Multiple bolus 30 mg; bolus 10–30 mg + infusion
200 mg/h; infusions 100–300 mg/h; bolus 100 mg + infusion 3–4 mg kg-1h-1;
1.5–2 mg/kg bolus twice ? infusion
3–4 mg kg-1h-1
48
↓ BP (5.5%)
Agitation
Perioral paraesthesias
-
-
(46) (47) (48)
NEUROPATHIC PAIN
3 mg/kg bolus + infusion
148
-
-
Lightheadedness (54.5%), drowsiness,
sedation (15.4%), dizziness (40%),
tinnitus, slurred speech, dysarthria
(77.8%), tremor (40%), weakness, (11.1%)
Nausea
(44.4%)
-
(49)(50) (51)(52)(53)
including postoperative
and post-stroke pain
4 mg/min for 1 h; 2 mg/kg infusion for 24 h;
200 mg or 5 mg/kg; 5 mg/kg for 30 min;5 mg/kg (180–450 mg); 1.5 mg/kg bolus; 50–100 mg bolus + infusion 1–4 mg/min for
48 h; computer-controlled lidocaine infusion; 2 mg/kg and 5 mg/kg infusion over 45 min;500 mg in 60 min
feeling ‘drunk’, nystagmus (7.7%)
(54) (55)(56) (57) (58)
HEADACHE
Multiple 50 mg bolus up to 150 mg; 1 mg/kg
over 2 min {or placebo}; infusion 2 mg/min
up to 14 days infusion 2 mg/min 7–14 days
158
Transient
arrhythmia,
chest pain
symptomatic
↓ BP/HR
(1.5%)
Agitation
Unusual taste, perioral numbness,
tinnitus, oscillopsia (1.5%)
Nausea
diarrhoea
(3%)
↓ K**
(59) (60)
Migraine, cluster,
myofascial pain,
atypical facial pain;analgesic rebound
headache + status
migrainosus or migraine, chronic
tension type, new
daily persistent
headache
Painful i.v. sites
(9%), hot
flushes (1.5%)
(61) (62)
+, yes; -, no; ?, with or without; ↓, decreased; ↑, increased; *N, total number of patients on lidocaine; †HR, heart rate; ‡BP, blood pressure; §RR, respiratory rate;
¶VPC, ventricular premature complexes; **K, potassium.
502
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Table 3 Case reports involving neuropsychiatric side-effects with lidocaine treatment
Source
Sex, age
(years)
weight
(kg)
Lidocaine (dose, administration
route) and concomitant
therapies
Pathological condition
Adverse events
Recovery
time
Psychiatric
Neurological
Others
(64)
Male
700 mg s.c.
Orthopaedic condition
(shoulder)
euphoria, excitement
Jactitation, hand tremor
–
30 min*
54 kg
uncontrollable desire to talk,
sense of fullness in the head
sleepiness, diplopia, arm
numbness, sense of
intensification of sounds,
difficulty in speaking
(6)
Female
500 mg s.c. + hyaluronidase
Child delivery
Euphoria, doom anxiety,
uncontrollable necessity to
talk
Facial twitching, muscle
rigidity, disorientation
Transitory facial cyanosis
4 h*
34 years
(pudendal nerve block)
54 kg
(65)
Female
31 years
2 ¥ 100 mg i.v. bolus + infusion
6.567 mg i.v. /24 h + other
meds.
Elective uterine curettage,
vaginal hysterectomy and
colposcopy
Agitation
Somnolence
Tachyopnoea
?†
(8)
Male
41 years
1st: 100 mg i.v. bolus + infusion
600 mg i.v. /4 h
Hepatic insufficiency + periods
of ventricular tachycardia
1st: –
1st: Coma, decerebrate posture,
increased tonus, bilateral
BBK‡
–
1st < 24 h
2nd < 3 h
2nd: infusion 800 mg i.v. /6 h
2nd: Agitation, confusion
2nd: Dysarthria, diplopia,
nystagmus, ataxia, hyperreflexia
(66)
Male
80 mg + 80 mg i.v. bolus +
infusion 3.3–6.7 mg/min i.v. + digoxin
Paroxysmal ventricular
tachycardia + acute
myocardial infarction
Euphoria
Facial twitching, petit mal and
grand mal seizures
Chest pain, respiratory arrest,
cardiac standstill, death
–
48 years77 kg
(67)
Male
Infusion 550 mg i.v. /3.5 h
(2 mg kg-1h-1) + procainamide
Paroxysmal ventricular
tachycardia
Restlessness, delirium with
visual hallucinations
–
–
20 min
66 years
(68)
Male
47 years
85 mg i.v. bolus + infusion
2 mg/min i.v. (12 days)
Acute myocardial
infarction + ventricular
fibrillation
Euphoria
Drowsiness, generalized
tonic-clonic seizures
Warmth (vasodilatation)
–
Female
69 years
100 mg i.v. bolus + infusion
2 mg/min i.v. (12 days)
Supraventricular
tachycardia + ventricular
extrasystoles
Euphoria
Drowsiness
Warmth (vasodilatation)
?
(69)
Female
Infusion 200 mg i.v. /35 min
Adiposis dolorosa (Dercum’s
disease) + systemic lupus
erythematosus
Euphoria
Hypnotized appearance,
numbness
Heat, flushing of breasts,
headache
?
48 years 66 kg
(70)
Female
40 years
100 mg i.v. bolus + infusion
2 mg/min i.v.
(3½ h) + propranolol
Ventricular tachycardia
Hysteria, aggressiveness
–
–
15 min
(71)
Female
1200 mg p.o.
Oesophageal stricture (elective
endoscopic dilatation)
Agitation, acute delirium
Disorientation
Sinus tachycardia
4 h
74 years
(accidental)
31 kg
(72)
Male
55 years
125 mg i.v. bolus + infusion
2 mg/min i.v. for 4 h
Premature ventricular
beats + congestive heart
failure
Psychosis
–
–
?
Male
? infusion i.v. for 2 days
Acute myocardial infarction
Anxiety, visual hallucinations,
paranoid ideation, psychosis
–
–
2 days
53 years
Male
Infusion 2 g i.v. for 1 day
Digitalis intoxication
Delusions, psychosis
–
–
?*
59 years
Male
Infusion 1.6 g i.v. for 12 h
Premature ventricular beats
Anxiety, hallucinations,
delirium
–
–
?
59 years
Male
Infusion 3 mg/min
i.v. + digoxin, morphine
Premature ventricular
beats + myocardial infarction
Acute psychosis
–
–
?
75 years
Female
100 mg i.v. bolus +
Recurrent ventricular
tachycardia
Agitation, excitement,
aggressive
–
–
25 min
48 years
2 mg/min i.v.
infusion + propranolol
(73)
Male
1.5 mg/kg bolus + infusion
20 mg kg-1min-1+ propranolol,
hydrochlorothiazide
Acute myocardial infarction
Marked confusion
Paraesthesia
–
?
56 years
(74)
Female
60 years
80 mg i.v. bolus +
200 mg i.v. bolus
Acute myocardial
infarction + ventricular
extra-systoles
Visual hallucinations,
persecutory delirium,
agitation
Weakness, visual disturbances
–
?
Lidocaine and headache
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Table 3 (Continued)
Source
Sex, age
(years)
weight
(kg)
Lidocaine (dose, administration
route) and concomitant
therapies
Pathological condition
Adverse events
Recovery
time
Psychiatric
Neurological
Others
(75)
Female
i.v. infusion
Cardiac patients treated for
arrhythmias (12 had severe
concurrent events thatcould contribute to
psychiatric symptoms:
congestive heart failure
(6 pts), persistent
hypotension (1 pt),
digitalis intoxication,
hyperthyroidism, electrolyte
disorder, treatment with
other anti-arrhythmic or
morphine sulphate)
Delusions
Confusion, disorientation
–
?
68 years
51 mg kg-1min-1
45 kg
Male
i.v. infusion
Hallucinations, delusions,
anxiety
Confusion, disorientation
–
?
49 years
51 mg kg-1min-1
75 kg
Male
i.v. infusion
Death fears, anxiety, agitation
–
Shortness of breath
30 min*
56 years
33 mg kg-1min-1
111 kg
Female
i.v. infusion
Death fears, anxiety
Confusion, disorientation
–
?
81 years
47 mg kg-1min-1
54 kg
Male
i.v. infusion
Death fears, illusions,
depression
–
–
?
79 years
64 mg kg-1min-1
59 kg
Male
i.v. infusion
Death fears, illusions, anxiety
Confusion, disorientation
–
?
61 years
31 mg kg-1min-1
87 kg
Male
i.v. infusion
Death fears, anxiety
Confusion, disorientation
–
?
52 years
54 mg kg-1min-1
78 kg
Male
i.v. infusion
Death fears, illusions,
depression
–
–
Days
50 years
56 mg kg-1min-1
76 kg
Male
i.v. infusion
Death fears
–
–
?
79 years
72 mg kg-1min-1
50 kg
Male
i.v. infusion
Hallucinations, delusions,
anxiety, hostility
Confusion, disorientation
–
?
70 years
322 mg kg-1min-1
57 kg
Male
i.v. infusion
Death fears, anxiety,
depression
–
–
?
70 years
61 mg kg-1min-1
73 kg
Male
i.v. infusion
Death fears, delusions,
anxiety, depression
Confusion, disorientation
–
?
70 years
62 mg kg-1min-1
87 kg
Male
i.v. infusion
Death fears, anxiety
Numbness, arm paralysis,
difficulty in talking
Blurred vision
*
66 years
52 mg kg-1min-1
74 kg
Male
i.v. infusion
Death fears, hallucinations,
anxiety, depression
Confusion, disorientation
–
?
66 years
78 mg kg-1min-1
54 kg
(76)
Male
300 mg s.c.
Endarterectomy
Agitation, incoherent speech
Tremor of both legs
Tachycardia, high blood
pressure
minutes
74 years
(90% stenosis of left
internal carotid art.)
70 kg
(77)
Male
29 years65 kg
600 mg s.c./20 min
Redundant prepuce
(circumcision, penile block)
Visual and auditory
disturbances, talkative,
restlessness, agitation,
psychosis
Headache, tinnitus, facial
twitching, trismus, limb
rigidity
Tachycardia, high blood
pressure
5 h
(78)
Female
0.5 ml 2% s.c. + triamcinolone
Cheloid abdominal scar
Death fears, anxiety, agitation
Muscular rigidity
Face erythema
15 min
13 years
*Insight maintained (after recovery).
†Unknown.
‡BBK, Babinski sign.
504
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and the literature at large suggest that patients
being considered for i.v. lidocaine should be
warned that psychiatric side-effects are possible,
and may be disturbing for both patient and carers.
Neurological side-effects with lidocaine have
been recognized for many years, with the initial
description of generalized tonic-clonic seizures in
two surgical patients in a series of 853, an incidence
of 0.2% (79). Apart from nausea in two patients,
there were no other major unwanted events (79).
Several reports have been published over the years
describing mechanisms that might induce systemic
toxicity when using lidocaine for local, subcutane-
ous, topic or infiltrative, anaesthesia (6, 7, 64, 77, 78,
80). These might be due to increased systemic
absorption of the drug, either by failure to add
adrenaline to the local solution (6, 79), excessive
dosage (79), highly vascularized injection site (77,
80) or accidental i.v. or oral administration (70, 80).
Absorption through mucous membranes dimin-
ishes the hepatic metabolism of lidocaine by avoid-
ing the first-pass effect (81). Other causes of
decreased drug metabolism are hepatic insuffi-
ciency, congestive heart failure (1, 8, 10, 38, 39) or
concomitant use of other drugs that might either
involve the P450 cytochrome system, such as cime-
tidine, alter haemodynamic status, such as propra-
nolol, or have the same profile of side-effects, such
as procainamide (1, 10, 32, 67, 70, 73). More than
half of reviewed case reports with psychiatric mani-
festations had concurrent disorders or medications
that could theoretically facilitate toxicity. Interest-
ingly, in our headache series 13 patients had con-
comitant prophylactic therapy with antiepileptics
(n = 11), b-blockers (n = 2) and tricyclic antidepres-
sants (n = 4). However, none of these therapies
influenced theoccurrence
adverse events in our series.
The purpose of our review was to document the
effects of the use of lidocaine not as a local anaes-
thetic, but as a systemic, i.v. treatment. Generally,
toxic reactions to either local (subcutaneous) or i.v.
administration probably differ only in the time-
frame they occur (80), although there is evidence
supporting the existence of local direct neurotoxic-
ity of intrathecal administration of lidocaine for
spinal anaesthesia (82, 83).
The case series reviewed are quite heterogeneous
in patient selection, pathologies involved and mode
of lidocaine administration, and discrepancies in
side-effect reports would therefore be expected.
Another fact contributing to this variability was
each author’s notion of relevance of side-effects. For
example, mild sedation, lightheadedness, dizziness,
ofneuropsychiatric
tinnitus, paraesthesias and twitching, nausea or
minor heart rate or blood pressure changes are
often viewed as normal effects of lidocaine and are
not considered unwanted or secondary (16, 27, 35,
37, 43, 46). Patients themselves often do not report
these symptomsspontaneously,
involved in clinical trails (37, 38, 50). Our review of
the literature suggests that most authors actively
seek out neurological and cardiovascular effects,
whereas psychiatric are often not mentioned (15, 28,
38, 41, 43, 46, 50).
Central nervous system toxicity is 0.3–100% in the
published series (14, 16, 17, 21). The clinical pattern
of this type of symptomatology seems to be stereo-
typed and progressive, but sometimes psychotic
reactions are described either with minimal or
without neurological manifestations (67, 68, 70–73).
This is also the case in our series, in which four
patients (20%) had marked psychiatric symptoms
that precluded further utilization of lidocaine but
had no neurological symptoms. In our series the
occurrence of neuropsychiatric adverse events was
75%, which is high when compared with the low
occurrence, 1.5% (59) to 29% (62), or total absence
(60) of this type of side-effect in other headache
series. Data from series with cardiac or other
pathologies are unhelpful in this regard because of
the encompassing range of 0.3–100% of patients with
the effect. Of note, SUNCT/SUNA patients seem to
have a higher rate of psychotic side-effects than other
headache patients (64% vs. 33%), although the
numbers are too small to draw any definite conclu-
sion. This difference could not be accounted for in
the previous history of depression or psychiatric
illness, absence or presence of beneficial therapeutic
effect on headache, presence or absence of other
side-effects, infusion doses or duration, or age. It is a
clinical point to bear in mind when considering
SUNCT/SUNA patients for such a treatment.
The toxic i.v. dose of lidocaine has been described
as > 4–8 mg/kg of body weight (6, 64). Two studies
(10, 39) determined signs of toxicity when blood
levels were > 5.9 mg/ml and 5.0 mg/ml, respectively,
but only studied the blood levels of toxic patients.
Other authors have reported on the importance of
rate of infusion in determining toxicity (19, 28).
Drayer and colleagues (32) evaluated serum levels
of lidocaine and its metabolites monoethylglycin-
exylidide (MEGX) and glycinexylidide (GX). They
reported six of 27 patients without toxicity symp-
toms with lidocaine levels > 8.0 mg/ml, whereas
five of six patients with toxic symptoms had levels
< 8.0 mg/ml. The difference observed between toxic
and non-toxic patients in this study was of higher
even when
Lidocaine and headache
505
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MEGX levels in toxic patients. Korbon et al. (20)
have suggested that there might be an individual
susceptibility for lidocaine toxicity, demonstrating a
significant decrease in experimental pain and toler-
ance in toxic vs. asymptomatic individuals. It is not
then clear whether side-effects can been attributed
to lidocaine itself or to its metabolites, MEGX and
GX (1, 32).
Animal electroencephalographic
have demonstrated rhythmic amygdaloid electric
activity after the administration of sub-convulsant
doses of lidocaine, sometimes spreading to the
fronto-orbital cortex, nucleus medialis dorsalis,
mesencephalic reticular formation, globus pallidus,
putamen and hippocampus. These discharges are
accompanied by vocalizations, respiratory changes
and a decrease in motor activity and in the response
to external stimuli. Cortical slow high-voltage activ-
ity would follow and outlast the amygdaloid
changes and could be related to staring and
stupor. Convulsant doses would produce focal dis-
charge from the amygdala and seizures, sometimes
preceded by behavioural alterations (84). These
observations lead to the hypothesis that the neu-
ropsychiatric effects of lidocaine in humans were
related to limbic hyperactivity with manifestations
similar to temporolimbic epilepsy, such as halluci-
nations, emotional and behavioural changes (85).
This hyperactivity could be related to the develop-
ment of lidocaine-induced pharmacological kind-
ling of the limbic system (86). A similar syndrome
occurs as an acute non-allergic reaction to procaine
penicillin, the Hoigné’s syndrome (86).
In conclusion, we have reported a series of
patients treated with i.v. lidocaine for primary
headache indications who developed neuropsychi-
atric symptoms. Half of the cohort had psychiatric
symptoms, some of which were highly disturbing,
and in one case a re-exposure established causality.
Our review of literature indicates that such prob-
lems have been recognized, although not in the
headache and pain literature. Because these symp-
toms do seem relatively common, and may be
disturbing, patients and physicians should be
aware that they might occur prior to commencing
treatment with i.v. lidocaine. We recommend rou-
tinely counselling patients and relatives of these
symptoms prior to treatment.
studies(84)
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