Headache 2008 the Authors Journal compilation 2008 American Headache Society

ISSN 0017-8748 doi: 10.1111/j.1526-4610.2008.01281.x Published by Wiley Periodicals, Inc.

Brief Communications
Intravenous Lidocaine in the Treatment of Refractory Headache: A Retrospective Case Series
Michael Marmura, MD; Noah Rosen, MD; Muhammad Abbas, MD; Stephen Silberstein, MD

Background.New treatments are needed to treat chronic daily headache (CDH) and chronic cluster headache (CCH). New treatments are needed to treat this population and intravenous (IV) lidocaine is a novel treatment for CDH. Objective.The aim of this study was to examine the use of IV lidocaine for refractory CDH patients in an inpatient setting. Methods.This was an open-label, retrospective, uncontrolled study of IV lidocaine for 68 intractable headache patients in an inpatient setting. We reviewed the medical records of patients receiving IV lidocaine between February 6, 2003 and June 29, 2005. Results.Pretreatment headache scores averaged 7.9 on an 11-point scale and posttreatment scores averaged 3.9 representing an average change of 4. Average length of treatment was 8.5 days. Lidocaine infusion was generally well tolerated with a low incidence of adverse events leading to discontinuation of treatment. Conclusions.This study suggests benet of lidocaine treatment and the need for further prospective analyses. The mechanism of lidocaine in treating headache is unknown. Key words: refractory headache, lidocaine, hemicrania continua, NSAIDs (Headache 2009;49:286-291)

Chronic daily headache (CDH), dened as a headache disorder that occurs more than 15 days a month for at least 3 months, is a common problem in neurology clinics. CDH includes patients with chronic migraine (CM), new daily persistent headache (NDPH), hemicrania continua (HC), and chronic tension-type headache (CTTH). CDH sufferers represent 4-5% of the general population and many, if not most of the patients seen in subspecialty
Jefferson Headache CenterDepartment of Neurology, Thomas Jefferson University, Philadelphia, PA, USA (M. Marmura, N. Rosen, M. Abbas, and S. Silberstein). Address all correspondence to M. Marmura, Jefferson Headache CenterDepartment of Neurology, Thomas Jefferson University, Philadelphia, PA, USA. Accepted for publication August 20, 2008.

headache practices.1,2 Patients with CDH are often difcult to treat and often require multiple drugs and nondrug treatment modalities. Other less common headaches, such as chronic cluster headache (CCH) with multiple daily attacks, can also be debilitating and difcult to treat. New treatments are needed to treat this refractory population.3 Previous studies have suggested that intravenous (IV) lidocaine is safe and effective in treating chronic pain disorders, including trigeminal neuralgia,4,5 diabetic neuropathy,6 and neuropathic pain.7 IV lidocaine has been used to treat patients with cancer pain unresponsive to opioids8 and to treat patients with spinal cord injury with central pain.9 A recent case report also stated that lidocaine is efcacious in treating SUNCT syndrome.10
Conict of Interest: None

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Headache Williams and Stark11 used IV lidocaine to treat CDH patients with medication overuse. Of 71 patients, 90% reported that daily headache was absent or improved immediately (70% at 6 months after the termination of treatment). The overused analgesic agent was successfully withdrawn in 97% of patients immediately (72% at 6 months). Only minor adverse events (AEs) were reported.11 We report our use of IV lidocaine in patients with CDH and intractable cluster headache who failed aggressive treatment. We developed our clinical protocol in collaboration with our cardiology colleagues and hospital administrators. This paper reviews our experience in the use of continuous administration of IV lidocaine over 2.5 years.

287 patients with no signicant AEs and minimal pain relief, we increased the dosage more rapidly. Some patients received doses as high as 4 mg/minute after nontoxic serum lidocaine levels were obtained. We attempted to keep the level below the upper limit of the therapeutic range for arrhythmia (5 mg/mL). Concurrent IV medications, including corticosteroids, NSAIDs, DHE, and antiemetics, were given as needed. Migraine preventive medications and medications for other medical conditions were continued. Patients were classied, based on their headache response, into complete responders when they become headache-free (0 on an 11-point [0-10] headache severity scale), partial responders if their score was 1 point or more below their baseline headache level, or nonresponders if there was no change. For each patient, we obtained age, gender, diagnosis, previous medication, history of medication overuse, IV lidocaine doses, duration of treatment, serum lidocaine levels, concurrent medications, and patient-rated 11-point headache rating scales. We extracted these data retrospectively and did not systematically query for side effects. The mean (SD) score difference between assessments (ie, post treatment minus baseline at admission) was measured and P value was determined with paired t-test. As the score differences were approximately normally distributed (P = .16, Shapiro-Wilk test), a 1-sample t-test used to test whether the mean score difference was less than zero (null hypothesis). We analyzed all available data points for these patients. If data such as headache scores were not available, we lowered the denominator appropriately and utilized the remaining data points. We obtained approval from our university Institutional Review Board for this study. The requirement for written informed consent was waived.

METHODS We conducted an open-label, retrospective chart review of all patients admitted to Thomas Jefferson University Hospital who received IV lidocaine for CDH or CCH between February 6, 2003 and June 29, 2005. The data were extracted in collaboration by 2 reviewers so results were not separately compared. Only patients who failed other aggressive inpatient treatments, including IV DHE, antiemetics, neuroleptics, corticosteroids, and nonsteroidal antiinammatory drugs (NSAIDs) (often in combination or sequentially), were treated. Contraindications included a history of signicant cardiac disease, arrhythmia, seizures, and previous allergic reactions to lidocaine. The off-label use of this medication was discussed with the patients and all gave informed consent. All patients had continuous cardiac monitoring during treatment. Vital signs (every 8 hours) and basic blood studies (complete blood count, basic chemistry panel, magnesium, and phosphate) and a daily 12-lead electrocardiogram (EKG) were also obtained. After the initial laboratory work and initial EKG were determined to be within an acceptable range, a standard peripheral IV was placed and the lidocaine infusion was started at a rate of 1 mg/ minute typically for 4 hours, after which it was raised to 2 mg/minute. The lidocaine dose was then titrated according to the patients response and tolerability after reviewing the serum lidocaine levels. For

RESULTS Sixty-eight CDH and chronic cluster patients, 59 women and 9 men, aged 17-66 years, (mean 39 years) were included. Of these, 41 had CM (with and without medication overuse), 12 had NDPH, 2 had CCH, and 13 had other headache disorders, including CTTH and medication overuse headache.

288 Most patients received other acute headache medications, including DHE, solumedrol, antiemetics, neuroleptics, anti-inammatories, and magnesium, as well as their oral preventive medication during their hospitalization, most before IV lidocaine was started. Most patients had overused acute medications, including opioids, butalbital, triptans, and NSAIDs. The average length of time of the lidocaine infusion was 8.5 days (range 2 to 15 days). The patients mean headache score was 7.9 on the 11-point severity scale prior to lidocaine and 3.9 post lidocaine infusion (average change was -4). Patients on lidocaine were signicantly more likely to improve than worsen (P < .001, 1 sample t-test). Based upon headache response criteria, 25.4% of patients exhibited a complete response, 57.1% exhibited a partial response, 3.2% worsened, and 14.3% exhibited no change during the lidocaine infusion. Among the partial responders, 20% showed signicant improvement (headache level 1-2 at discharge), 40% showed moderate improvement (headache level 3-4 at discharge), and 40% showed mild improvement (headache level 5-6 at discharge).The maximum lidocaine level was variable and as it did not correlate with percent improvement. We used it to minimize the risk of toxicity. The 2 patients with CCH had 50% reduction in their headache severity, neither became headache-free. Treatment was generally well tolerated; AEs, when present, were mild and usually resolved after dose reduction (Table). Half of the patients experienced some AEs (including hallucinations,

February 2009 tachycardia, tremors, hypotension, light-headedness, phlebitis, line infection, and hypertension), but none caused the treatment to be aborted.

Table.Adverse Events

Event

Number of patients (of 78)

Nausea/vomiting Hallucinations Tachycardia Tremors Hypotension Light-headed Phlebitis Line infection Hypertension

14 8 4 3 2 1 1 1 1

DISCUSSION Chronic daily headache affects approximately 4% of the United States population. CDH can be subclassied on the basis of average headache duration. CDH of long duration (4 hours) includes CM, NDPH, CTTH, and HC. CDH of shorter duration (<4 hours) includes CCH, chronic paroxysmal hemicrania, hypnic headache, idiopathic stabbing headache, and the cranial neuralgias. CDH, particularly CM, NDPH, and HC, can be associated with medication overuse. Studies assessing the risk factors for migraine found that the prevalence of CDH decreased slightly with age and increased in women and individuals who were divorced, separated, or widowed. Persons with less than a high-school education face a 3-fold greater risk for CDH than persons who possess a graduate-level education. CDH is also associated with diagnoses of arthritis and diabetes and with medication overuse.12,13 CDH presents a diagnostic and therapeutic challenge to primary care physicians and neurologists and impacts patients and their families. Both direct and indirect costs need to be considered. Migraine costs American employers about $13 billion a year. Direct medical costs for migraine, which include prescription but exclude over-the-counter medications, are approximately $1 billion in the United States.14 The trigeminal autonomic cephalalgias comprise many of the CDHs of less than 4 hours in duration and are also very debilitating. Limited options exist for patients with CCH and for those with SUNCT. They cause signicant disability and secondary economic burden. Lidocaine has been used as an acute treatment option for many types of headache. Disagreement exists in its dosing, timing, and mode of administration. Lidocaine has been used by the nasal route, by suppository, and by intramuscular injections in addition to IV use. Occipital, supraorbital, and supratrochlear nerve blocks and trigger point injections with lidocaine are used for the acute treatment of

Headache migraine.15 Kudrow et al have reported a successful response of migraine attacks to lidocaine treatment is more likely to occur in patients having only migraine, when compared with migraine patients who had daily dull headaches; the difference was not signicant. Unilateral attacks, however, were signicantly more treatment-responsive when compared with bilateral attacks.16 Maizels et al reported that intranasal lidocaine 4% was better than placebo.17 Maizels also stated in a case report that intranasal lidocaine consistently prevented the development of headache symptoms following aura.18 Amir suggests that because intranasal lidocaine is highly irritative, it could easily be distinguished from saline that was used as a control, and the treatment response could be from lack of blinding.19 Better results have been reported with IV lidocaine, although acute treatment may be less effective. Burke used 1% lidocaine injection intravenously over 90 seconds at a dose not exceeding 1 mg per kg for classic and common migraines with some success,20 but Reutens reports that lidocaine failed to prove superiority to placebo after 20 minutes of infusion at a rate of 1 mg/kg.21 Jauslin et al reported that IV lidocaine is often effective in 2 days and can be combined with IV DHE in patients with CDH.22 Matharu et al have recently presented evidence that SUNCT syndrome appeared to be controlled by IV lidocaine during the period of infusion.10 Schere and Silberstein report that IV lidocaine can treat postacoustic neuroma resection headache.23 The mechanism by which lidocaine affects headache pain is unknown. Animal models suggest that lidocaine may interrupt a portion of the nociceptive pathway.24,25 There may be effect via NMDA receptors or sodium channels.26 IV lidocaine after colorectal surgery demonstrated signicant decreased length of stay, improved gastrointestinal motility, and decreased plasma levels of pro-inammatory cytokine and complement levels.27 Our study suggests that prolonged lidocaine infusion may be effective in CDH to decrease or eliminate pain and improve function. We treated our most recalcitrant patients those who have failed to respond to standard abortive and aggressive treatments including inpatient DHE or neuroleptics.

289 Given our results, there is a need for prospective controlled studies comparing IV lidocaine to other aggressive treatments. Our AEs were minimal and produced no dropouts. The incidence of neuropsychiatric AEs has been examined in a small series from Gouveia and Goadsby and may be due to limbic hyperactivity, but was rarely seen as cause for discontinuation of treatment in our population.28 There are limitations to our retrospective study. It was an open-label and unblinded study and the patients expectations were high. Neither the length of treatment nor the absolute lidocaine level attained correlated to nal outcome. Multiple concurrent medications were given. Most of the patients treated had their IV lidocaine treatment terminated because of either complete headache improvement or treatment greater than 14 days. None had intolerable AEs but this study was underpowered to detect any but the most common AEs. Failure to respond was the primary criteria used to increase the dose of lidocaine; thus, we cannot answer the question of whether a higher therapeutic drug level or dosage adjustment actually mattered. The length of treatment and the requirement for monitoring preclude this care from many patients. Antiarrthymic agents such as lidocaine can cause new or worsen existing arrthymias, and most commonly increased preventricular contractions or ventricular tachycardia.29 Because of this, patients on IV lidocaine receive telemetry monitoring. Given the use of similar agents with potential proarrhytmic effects such as mexiletine and phenytoin, it is unclear that lidocaine treatment requires telemetry, especially for patients tolerating a stable dose. Further research is needed to evaluate this form of treatment on a less recalcitrant population and analyze whether shorter lengths of infusion or lower doses may be more effective in a more common population. In a larger, prospective study, concomitant medications could be avoided to help determine the sole effect of lidocaine. Despite the limitations of the study, the positive outcome is enough to suggest that further research is necessary. Given the degree of disability these patients suffer, it is important to help develop further means of treatment.

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CONCLUSION Intravenous lidocaine may be a safe and effective treatment for patients with refractory CDH as well as CCH. Patients with CM, NDPH, and other daily headache subtypes may benet from treatment. AEs appear infrequent and minimally limiting of treatment. Shorter treatment lengths would allow IV lidocaine to be more feasible in treating the general headache population. REFERENCES
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