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doi:10.1111/j.1468-2982.2008.01800.

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; 29:496508. 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 symptoms being reported in 1.8100%. 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 substantial concern for neurologists and headache specialists being that of cardiac side-effects. Lidocaine is metabolized by the microsomal enzyme system in the liver and excreted in the urine; after intravenous (i.v.) administration lidocaine plasma concentration describes a biphasic curve, with an early rapid fall around 817 min and a second slow decrease around 87108 min (1). Lidocaine exerts its action through sodium channel blockade and subsequent suppression of cellular excitability (4). The effect of lidocaine in headache
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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, sweating, weakness, heavy respirations, muscle twitching, euphoria, agitation, difficulty in concentrating and speaking, dysarthria, diplopia, psychotic reactions, shaking and eventually generalized convulsions 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.
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Lidocaine and headache We also performed a literature review on i.v. lidocaine-induced toxicity. Our purpose was to evaluate lidocaine toxicity and its side-effect prole, with special reference to neuropsychiatric symptoms, in order to highlight the problem for the headache community.

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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 evaluation, 12-lead electrocardiogram and routine biochemical tests with liver enzyme level estimations. Cardiac monitoring and uid chart balance were maintained during the course of the infusion. The treatment consisted of a constant infusion of a 0.4% lidocaine solution2 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-1 h-1), if required. At the start and at each dose escalation, pulse rate and blood pressure were measured every 5 min for the rst 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 110, or tabulation of attacks for short-lasting headaches, 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 classied into four major groups including cardiovascular, neuropsychiatric, gastrointestinal and other symptoms. Neuropsychiatric events were further classied into neurological or psychiatric, or both, according to their main characteristics. A full description of the clinical features is included in the Results section.
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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 regressing against headache type, days of treatment, presence of a psychiatric history, age and sex, signicance was assessed at P < 0.05 with the HosmerLemeshow goodness-of-t statistic (12).

Literature review
We performed a MEDLINE search in order to identify 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 psychiatric. 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 1965 years). Eleven of 20 patients (55%) had shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)/ short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) syndromes (13), four had migraine (two chronic migraine and two chronic migraine with medication overuse) and ve had other headache types. The latter included chronic post-traumatic headache, glossopharyngeal neuralgia, idiopathic stabbing headache, trigeminal dysaesthesia and pituitary tumour-associated headache (Table 1). Investigations Patient electrocardiograms demonstrated normal sinus rhythm and no signicant conduction abnormalities. Blood tests were within normal ranges with the exception of ve 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


Infusion rate (mg/min) Side-effects Cardiovascular + + + S* + + Psychiatric Neurological Gastrointestinal Other Maximum 3.7 2 3.7 No + Toxic Previous psychiatric history Headache prophylaxis (daily dosage) Headache relief + 7 2 Infusion duration (days)

Sex

Age

Headache diagnosis

R Gil-Gouveia & PJ Goadsby

F F

61 30

SUNCT SUNCT

M M F F + 6 4 4 + + S* -

52 49 36 54

SUNCT SUNCT SUNCT SUNCT

+ + + + 7 5 5 7/5 4 3 4 3 4 2 4 2.7

+ -

+ +

+ S* + S* + S*

+ +

+ + + -

+ -

59

SUNCT

(1600 mg) (2400 mg) (300 mg) (150 mg) (2700 mg) (160 mg) (800 mg) (400 mg) (100 mg) (2400 mg) (200 mg) (25 mg) (800 mg) (3600 mg) (600 mg) (50 mg) + + 7 9 7 7 8 6 4 No + 3 4 2 3 + 3 3 3 3 3 3 + + + + + + + + + 4 4 7 2 3 4 2 3 3 + + + S* + + -

F M M

51 65 50

SUNCT SUNCT SUNCT

M F F (30 mg) VPA (400 mg) TPM (100 mg) TAD (125 mg)

34 28 62

GBP GBP DPH TAD GBP bB CBZ LTG TPM GBP CBZ bB CBZ GBP LTG TAD TAD + + S* + + + + -

+ -

F M

28 35

46

F F

49 54

10 5 3 4

+ -

2 4

+ + S*

+ +

+ -

F TPM (250 mg) + 6

25

3 3

++

+ S*

+ -

19

SUNCT/ SUNA Pituitary headache Trigeminal dysaesthesia Status migrainosis Post-traumatic headache Chronic migraine with analgesic overuse Chronic migraine Hemiplegic migraine with analgesic overuse Glossopharyngeal neuralgia Idiopathic stabbing headache

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+, 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.

Lidocaine and headache 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 previously unsuccessful was 10, ranging from three to 20. The most frequent previously used drugs were amitriptyline (18/20), gabapentin (15/20), carbamazepine and topiramate (13/20), sodium valproate (12/20), indomethacin (12/20), lamotrigine and corticosteroids (10/20). Other drugs frequently used included verapamil, pizotifen, propranolol, methysergide and morphine. The range of medicines previously 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 comorbidities included severe active Crohns disease, active ischaemic optic neuropathy, benign pituitary 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 Bells palsy at age 12 years. 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: chlorpromazine (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
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included: gabapentin (n = 5), carbamazepine (n = 3), topiramate (n = 3), lamotrigine (n = 2), phenytoin (n = 1), sodium valproate (n = 1), tricyclic antidepressants (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). Other treatments included methotrexate, vitamin supplements, antiasthma inhalators and antispasmodics or other drugs altering gut motility. Patients less likely to benet from lidocaine infusion were on prophylaxis with tricyclic antidepressants (c2 4.804, P = 0.028). Phenytoin prophylaxis was also related to lower benet 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 inuence the therapeutic response to lidocaine.

Adverse events on lidocaine


All patients suffered some type of adverse event, but none was considered serious or lifethreatening. 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 c2 3.810, P = 0.051; psychiatric c2 0.000, P = 1.000; neurological c2 0.000, P = 1.000; gastrointestinal c2 0.848, P = 0.357; and other c2 0.317, P = 0.573). When analysing each preventive in isolation, two medications were related to the occurrence of cardiovascular eventsgabapentin (c2 6.667, P = 0.01) and tricyclic antidepressants (c2 5.000, P = 0.025), although again the numbers were small. No other agent inuenced any other type of event, not even b-blockers. Analysis was also performed grouping preventives into antiepileptics in general, enzymatic inductor antiepileptics and antiepileptics with action on sodium channels. Still, we found no evidence of inuence of these medications on the occurrence of adverse events.

500

R Gil-Gouveia & PJ Goadsby complained of constipation. Two patients had transient 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 inltration 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.

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 (215 h). One case had an episode of self-limited atrial brillation 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 ideation (n = 2) and agitation with visual and auditory hallucinations (n = 5). One patient with SUNCT with marked paranoid ideation had such an excellent clinical response that she requested the infusion 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 signicant (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 drowsiness (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. Taken together, neuropsychiatric symptoms occurred in 15 of 20 (75%) patients that we treated. Gastrointestinal adverse events The principal gastrointestinal adverse event registered was nausea (n = 6), and two patients

Review of literature
Results from the literature review on unwanted effects of i.v. lidocaine treatment in adults are presented in Table 2, including only case series (9, 10, 1463). It includes 50 series and around 6000 patients treated for different reasons: surgical patients (for anaesthesia), pain and headache patients (for analgesia), 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 cardiovascular arrest (16, 28, 37). Psychiatric side-effects are reported in 1.8100% (17, 27). Table 3 describes case reports on psychiatric effects of lidocaine, independently of route of administration (6, 8, 6471, 7378). It includes 17 reports involving 36 patients, mostly male (69%) adults with cardiac disorders (78%). Most of these toxicity reports involve i.v. administration of lidocaine (8, 6569, 7375), but some are due to subcutaneous (6, 64, 7678) or oral (accidental) (71) administration. Twenty patients (56%) had concurrent conditions or administration of other drugs that could inuence lidocaine toxicity. The psychiatric symptoms include excitement, euphoria and agitation, sometimes evolving to doom anxiety, delirium and frank psychosis with hallucinations.

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 contrast 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


Side-effects (maximum % reported)

Patients

Source Anaesthesia with succinyldicholine+lidocaine; Intermittent dosage (0750 mg); 800 mg/2 days, or placebo or 1757 Sleepiness, drowsiness, seizures (0.3%) Nausea Vomits (16.5%) 500 mg i.m. + 1000 mg i.v. 45 Euphoria (100%) BP -

Pathology

Lidocaine i.v. administration N* Cardiovascular Psychiatric Neurological Other

Gastrointestinal

(14) (15)

Warmth

(16)

(17)

(18)

(19)

SURGICAL PATIENTS Various major and minor short-term surgical procedures; patients with postoperative pain 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-1 min-1 HR (80%) or (10%); BP (90%)

RR (30%) or (40%)

(20) 12 mg bolus; 1.5 mg/kg bolus infusion 0.030.05 mg kg-1 min-1; 12 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%) 58 BP/HR (4.1%), VPC (2%) Heart block (7.7%), HR /BP (12.5%), BP (23.6%), cardiac arrest (1.4%) Euphoria (1.8%), confusion, agitation (9.7%), psychosis

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Nausea (10%) 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%) 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%) Drowsiness, sedation, stupor and dysarthria (4.1%) Nausea (2%) Diaphoresis (11.1%) 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 25100 mg bolus + infusion 0.510 mg/min; 25100 mg multiple bolus 1034 Nausea Rash, phlebitis (0.4%), syncope, apnoea (1.4%) 12 mg/kg bolus infusion 12 mg/min; 13 mg/kg single or multiple bolus; infusion 0.0150.045 mg kg-1 min-1 up to 5 days; 50 mg 100 mg bolus infusion 1 mg/min for 24 h; ?bolus + infusion 1555 mg kg-1 min-1 2668 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 (11%) PR interval (4.4%), heart Block, BP/ HR (2.9%) cardiac arrest (4%) Difficulty breathing (1.5%), RR, Respiratory arrest (0.7%) 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%) 25150 mg bolus infusion 14 mg/min; 25150 mg bolus infusion 0.54 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 14 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}

(21) (22) (23)

CARDIAC ARRHYTHMIAS

(24)

(25)

(26)

(10) (27) (28) (29)

Various types of acute and chronic ventricular arrhythmias CARDIAC ARRHYTHMIAS Ventricular arrhythmias after cardiac surgery CARDIAC ARRHYTHMIAS

(30)

(31)

(32)

(33)

(34)

(35)

Ventricular arrhythmias + ischaemic heart disease; (750 hospitalized old patients, age average 65 years and 27 cocaine-induced acute myocardial infarction) ISCHAEMIC HEART DISEASE

(36)

(37)

(38)

(39)

(40)

Lidocaine and headache

(41)

(42)

501

(43)

Coronary ischaemic disease or acute myocardial infarction (18 with heart failure)

502

Table 2 (Continued)
Side-effects (maximum % reported)

Patients

Source 1.5 mg/kg bolus {or placebo} 11 -

Pathology

Lidocaine i.v. administration N* Cardiovascular Psychiatric Neurological

Gastrointestinal

Other -

(44)

(45) 48 Agitation Perioral paraesthesias

R Gil-Gouveia & PJ Goadsby

(46)

BRONCHOSCOPY under general anaesthesia EPILEPSY and STATUS EPILEPTICUS BP (5.5%)

(47) 148 -

NEUROPATHIC PAIN

Multiple bolus 30 mg; bolus 1030 mg + infusion 200 mg/h; infusions 100300 mg/h; bolus 100 mg + infusion 34 mg kg-1 h-1; 1.52 mg/kg bolus twice infusion 34 mg kg-1 h-1 3 mg/kg bolus + infusion

Lightheadedness (54.5%), drowsiness, sedation (15.4%), dizziness (40%), tinnitus, slurred speech, dysarthria (77.8%), tremor (40%), weakness, (11.1%) feeling drunk, nystagmus (7.7%)

(48) (49) (50) (51) (52) (53)

Nausea (44.4%)

(54)

including postoperative and post-stroke pain

(55)

(56)

(57) 158 Transient arrhythmia, chest pain symptomatic BP/HR (1.5%)

(58) (59) (60)

HEADACHE

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 (180450 mg); 1.5 mg/kg bolus; 50100 mg bolus + infusion 14 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 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 714 days Agitation

Unusual taste, perioral numbness, tinnitus, oscillopsia (1.5%)

Nausea K** diarrhoea (3%) Painful i.v. sites (9%), hot ushes (1.5%)

(61)

(62)

Migraine, cluster, myofascial pain, atypical facial pain; analgesic rebound headache + status migrainosus or migraine, chronic tension type, new daily persistent headache

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+, 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.

Table 3 Case reports involving neuropsychiatric side-effects with lidocaine treatment


Adverse events Pathological condition Orthopaedic condition (shoulder) euphoria, excitement uncontrollable desire to talk, sense of fullness in the head Euphoria, doom anxiety, uncontrollable necessity to talk Agitation Somnolence Tachyopnoea 1st: 2nd: Agitation, confusion Euphoria Drowsiness, generalized tonic-clonic seizures Drowsiness Hypnotized appearance, numbness Disorientation Anxiety, hallucinations, delirium Acute psychosis Agitation, excitement, aggressive Marked confusion Paraesthesia Weakness, visual disturbances Acute myocardial infarction + ventricular extra-systoles Visual hallucinations, persecutory delirium, agitation Transitory facial cyanosis Psychiatric Neurological Others Recovery time 30 min*

Source

Sex, age (years) weight (kg)

Lidocaine (dose, administration route) and concomitant therapies

(64)

Male 54 kg

700 mg s.c.

(6)

500 mg s.c. + hyaluronidase Child delivery (pudendal nerve block)

Jactitation, hand tremor sleepiness, diplopia, arm numbness, sense of intensication of sounds, difficulty in speaking Facial twitching, muscle rigidity, disorientation

4 h* ? 1st < 24 h 2nd < 3 h

(65)

Female 34 years 54 kg Female 31 years Elective uterine curettage, vaginal hysterectomy and colposcopy Hepatic insufficiency + periods of ventricular tachycardia

(8)

Male 41 years

2 100 mg i.v. bolus + infusion 6.567 mg i.v. /24 h + other meds. 1st: 100 mg i.v. bolus + infusion 600 mg i.v. /4 h

2nd: infusion 800 mg i.v. /6 h

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1st: Coma, decerebrate posture, increased tonus, bilateral BBK 2nd: Dysarthria, diplopia, nystagmus, ataxia, hyperreexia Facial twitching, petit mal and grand mal seizures Chest pain, respiratory arrest, cardiac standstill, death Warmth (vasodilatation) Warmth (vasodilatation) Heat, ushing of breasts, headache Sinus tachycardia 20 min ? ? 15 min 4h ? 2 days ?* ? ? 25 min ? ? Restlessness, delirium with visual hallucinations Euphoria Euphoria Euphoria Hysteria, aggressiveness Agitation, acute delirium Psychosis Paroxysmal ventricular tachycardia + acute myocardial infarction Paroxysmal ventricular tachycardia Acute myocardial infarction + ventricular brillation Supraventricular tachycardia + ventricular extrasystoles Adiposis dolorosa (Dercums disease) + systemic lupus erythematosus Ventricular tachycardia Oesophageal stricture (elective endoscopic dilatation) Premature ventricular beats + congestive heart failure Acute myocardial infarction Digitalis intoxication Premature ventricular beats Premature ventricular beats + myocardial infarction Recurrent ventricular tachycardia Acute myocardial infarction Anxiety, visual hallucinations, paranoid ideation, psychosis Delusions, psychosis

(66)

(67)

(68)

Male 48 years 77 kg Male 66 years Male 47 years

80 mg + 80 mg i.v. bolus + infusion 3.36.7 mg/min i.v. + digoxin Infusion 550 mg i.v. /3.5 h (2 mg kg-1 h-1) + procainamide 85 mg i.v. bolus + infusion 2 mg/min i.v. (12 days)

Female 69 years

100 mg i.v. bolus + infusion 2 mg/min i.v. (12 days)

(69)

Infusion 200 mg i.v. /35 min

(70)

Female 48 years 66 kg Female 40 years

(71)

100 mg i.v. bolus + infusion 2 mg/min i.v. (3 h) + propranolol 1200 mg p.o. (accidental)

(72)

Female 74 years 31 kg Male 55 years

125 mg i.v. bolus + infusion 2 mg/min i.v. for 4 h

? infusion i.v. for 2 days

Infusion 2 g i.v. for 1 day

Male 53 years Male 59 years Male 59 years Male 75 years Female 48 years

Infusion 1.6 g i.v. for 12 h

Lidocaine and headache

(73)

Male

56 years

(74)

Female 60 years

Infusion 3 mg/min i.v. + digoxin, morphine 100 mg i.v. bolus + 2 mg/min i.v. infusion + propranolol 1.5 mg/kg bolus + infusion 20 mg kg-1 min-1 + propranolol, hydrochlorothiazide 80 mg i.v. bolus + 200 mg i.v. bolus

503

504

Table 3 (Continued)
Adverse events Pathological condition Delusions Hallucinations, delusions, anxiety Death fears, anxiety, agitation Death fears, anxiety Death fears, illusions, depression Death fears, illusions, anxiety Death fears, anxiety Death fears, illusions, depression Death fears Hallucinations, delusions, anxiety, hostility Death fears, anxiety, depression Death fears, delusions, anxiety, depression Death fears, anxiety Death fears, hallucinations, anxiety, depression Agitation, incoherent speech Confusion, disorientation Confusion, disorientation Numbness, arm paralysis, difficulty in talking Confusion, disorientation Tremor of both legs Headache, tinnitus, facial twitching, trismus, limb rigidity Visual and auditory disturbances, talkative, restlessness, agitation, psychosis Death fears, anxiety, agitation Muscular rigidity Confusion, disorientation Confusion, disorientation Blurred vision Tachycardia, high blood pressure Tachycardia, high blood pressure Face erythema Confusion, disorientation Shortness of breath Confusion, disorientation Confusion, disorientation Psychiatric Neurological Others Recovery time ? ? 30 min* ? ? ? ? Days ? ? ? ? * ? minutes 5h

Source

Sex, age (years) weight (kg)

Lidocaine (dose, administration route) and concomitant therapies

(75)

i.v. infusion 51 mg kg-1 min-1

i.v. infusion 51 mg kg-1 min-1

i.v. infusion 33 mg kg-1 min-1

R Gil-Gouveia & PJ Goadsby

i.v. infusion 47 mg kg-1 min-1

i.v. infusion 64 mg kg-1 min-1

Cardiac patients treated for arrhythmias (12 had severe concurrent events that could 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)

i.v. infusion 31 mg kg-1 min-1

i.v. infusion 54 mg kg-1 min-1

i.v. infusion 56 mg kg-1 min-1

i.v. infusion 72 mg kg-1 min-1

i.v. infusion 322 mg kg-1 min-1

i.v. infusion 61 mg kg-1 min-1

i.v. infusion 62 mg kg-1 min-1

i.v. infusion 52 mg kg-1 min-1

i.v. infusion 78 mg kg-1 min-1

(76)

300 mg s.c.

(77)

Female 68 years 45 kg Male 49 years 75 kg Male 56 years 111 kg Female 81 years 54 kg Male 79 years 59 kg Male 61 years 87 kg Male 52 years 78 kg Male 50 years 76 kg Male 79 years 50 kg Male 70 years 57 kg Male 70 years 73 kg Male 70 years 87 kg Male 66 years 74 kg Male 66 years 54 kg Male 74 years 70 kg Male 29 years 65 kg Endarterectomy (90% stenosis of left internal carotid art.) Redundant prepuce (circumcision, penile block) Cheloid abdominal scar

600 mg s.c./20 min

Blackwell Publishing Ltd Cephalalgia, 2009, 29, 496508

(78)

Female 13 years

0.5 ml 2% s.c. + triamcinolone

15 min

*Insight maintained (after recovery). Unknown. BBK, Babinski sign.

Lidocaine and headache 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, subcutaneous, topic or inltrative, 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 diminishes the hepatic metabolism of lidocaine by avoiding the rst-pass effect (81). Other causes of decreased drug metabolism are hepatic insufficiency, congestive heart failure (1, 8, 10, 38, 39) or concomitant use of other drugs that might either involve the P450 cytochrome system, such as cimetidine, alter haemodynamic status, such as propranolol, or have the same prole of side-effects, such as procainamide (1, 10, 32, 67, 70, 73). More than half of reviewed case reports with psychiatric manifestations had concurrent disorders or medications that could theoretically facilitate toxicity. Interestingly, in our headache series 13 patients had concomitant prophylactic therapy with antiepileptics (n = 11), b-blockers (n = 2) and tricyclic antidepressants (n = 4). However, none of these therapies inuenced the occurrence of neuropsychiatric adverse events in our series. The purpose of our review was to document the effects of the use of lidocaine not as a local anaesthetic, but as a systemic, i.v. treatment. Generally, toxic reactions to either local (subcutaneous) or i.v. administration probably differ only in the timeframe they occur (80), although there is evidence supporting the existence of local direct neurotoxicity 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 authors notion of relevance of side-effects. For example, mild sedation, lightheadedness, dizziness,
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505

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 symptoms spontaneously, even when 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 0.3100% in the published series (14, 16, 17, 21). The clinical pattern of this type of symptomatology seems to be stereotyped and progressive, but sometimes psychotic reactions are described either with minimal or without neurological manifestations (67, 68, 7073). 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 0.3100% 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 denite conclusion. This difference could not be accounted for in the previous history of depression or psychiatric illness, absence or presence of benecial 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 > 48 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 monoethylglycinexylidide (MEGX) and glycinexylidide (GX). They reported six of 27 patients without toxicity symptoms with lidocaine levels > 8.0 mg/ml, whereas ve 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

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2 Mao J, Chen LL. Systemic lidocaine for neuropathic pain relief. Pain 2000; 87:717. 3 Rosner S. A simple method of treatment for the acute headache. Headache 1984; 24:50. 4 Ragsdale DS, McPhee JC, Scheuer T, Catterall WA. Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science 1994; 265:17248. 5 Kaube H, Hoskin KL, Goadsby PJ. Lignocaine and headache: an electrophysiological study in the cat with supporting clinical observations in man. J Neurol 1994; 241:41520. 6 Goldman JA. A rare toxic effect of local anaesthesia with lignocaine: a case report. Br J Anaesth 1958; 30:3779. 7 Sadove MS, Wyant GM, Gittelson LA, Kretchmer HE. Classication and management of reactions to local anesthetic agents. JAMA 1951; 148:1722. 8 Selden R, Sasahara AA. Central nervous system toxicity induced by lidocaine. Report of a case in a patient with liver disease. JAMA 1967; 202:9089. 9 Scott DB. Toxic effects of local anaesthetic agents on the central nervous system. Br J Anaesth 1986; 58:7325. 10 Davison R, Parker M, Atkinson AJ Jr. Excessive serum lidocaine levels during maintenance infusions: mechanisms and prevention. Am Heart J 1982; 104:2038. 11 Matharu MS, Cohen AS, Goadsby PJ. SUNCT syndrome responsive to intravenous lidocaine. Cephalalgia 2004; 24:98592. 12 Hosmer DW, Lemeshow S. Applied logistic regression, 2nd edn. New York: John Wiley & Sons 2000. 13 Headache Classication Committee of the International Headache Society. The International Classication of Headache Disorders (second edition). Cephalalgia 2004; 24 (Suppl. 1):1160. 14 De Clive-Lowe SG, Gray PW, North J. Succinyldicholine and lignocaine by continuous intravenous drip; report of 1000 administrations. Anaesthesia 1954; 9:96104. 15 De Clive-Lowe SG, Desmond J, North J. Intravenous lignocaine anaesthesia. Anaesthesia 1958; 13:13846. 16 Bartlett EE, Hutserani O. Xylocaine for the relief of postoperative pain. Anesth Analg 1961; 40:296304. 17 Foldes FF, Molloy R, McNall PG, Koukal LR. Comparison of toxicity of intravenously given local anesthetic agents in man. JAMA 1960; 172:14938. 18 Scott DB. Evaluation of the toxicity of local anaesthetic agents in man. Br J Anaesth 1975; 47:5661. 19 Rowlingson JC, DiFazio CA, Foster J, Carron H. Lidocaine as an analgesic for experimental pain. Anesthesiology 1980; 52:202. 20 Korbon GA, Rowlingson JC, DiFazio CA. Sensitivity to pain predicts CNS sensitivity to lidocaine. Anesthesiology 1984; 61:7679. 21 Hayes JG, Ettinger E, Wanat FE, Killip T. Evaluation of lidocaine in the treatment of ventricular arrhythmia. Circulation 1967; 36 (Suppl. 2):137. 22 Grossman JI, Lubow LA, Frieden J, Rubin IL. Lidocaine in cardiac arrhythmias. Circulation 1967; 36 (Suppl. 2):126. 23 Anderson ST, Pitt A. Lignocaine in the management of ventricular arrhythmias. Med J Aust 1969; 1:20811. 24 Hilleman DE, Mohiuddin SM, Mooss AN, Hunter CB, Destache CJ, Sketch MH Sr. Comparative pharmacodynamics of intravenous lidocaine in patients with acute

MEGX levels in toxic patients. Korbon et al. (20) have suggested that there might be an individual susceptibility for lidocaine toxicity, demonstrating a signicant decrease in experimental pain and tolerance 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 studies (84) 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 activity would follow and outlast the amygdaloid changes and could be related to staring and stupor. Convulsant doses would produce focal discharge from the amygdala and seizures, sometimes preceded by behavioural alterations (84). These observations lead to the hypothesis that the neuropsychiatric effects of lidocaine in humans were related to limbic hyperactivity with manifestations similar to temporolimbic epilepsy, such as hallucinations, emotional and behavioural changes (85). This hyperactivity could be related to the development of lidocaine-induced pharmacological kindling of the limbic system (86). A similar syndrome occurs as an acute non-allergic reaction to procaine penicillin, the Hoigns syndrome (86). In conclusion, we have reported a series of patients treated with i.v. lidocaine for primary headache indications who developed neuropsychiatric 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 problems have been recognized, although not in the headache and pain literature. Because these symptoms 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 routinely counselling patients and relatives of these symptoms prior to treatment.

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