JOURNAL OF PALLIATIVE MEDICINEVolume 7, Number 5, 2004© Mary Ann Liebert, Inc.

Intravenous Lidocaine Relieves Severe Pain: Results of an Inpatient Hospice Chart Review

JAY THOMAS, M.D., Ph.D., ROBERT KRONENBERG, R.Ph., C.G., Pharm.D., MICHAEL CRAIG COX, Pharm.D., GILBERT C. NACO, M.D.,

MARK WALLACE, M.D., and CHARLES F. VON GUNTEN, M.D., Ph.D.

ABSTRACT

Background: Parenteral lidocaine has been reported to relieve neuropathic pain and/or painrefractory to opioid therapy.

Method: A retrospective chart review of 768 consecutive patients acutely admitted to a hos-pice inpatient unit was performed to assess the efficacy and tolerability of parenteral lido-caine for pain relief.

Results: Eighty-two patients (approximately 11%) received parenteral lidocaine. Typically,a patient received a parenteral bolus and pain relief was evaluated 30 minutes later. If therewas an effect, a continuous infusion was started. Sixty-one patients receiving lidocaine wereevaluable for pain relief response. Fifty patients (82% of evaluable patients) reported a ma-jor response of their pain to lidocaine. Five patients (8% of evaluable patients) reported a par-tial response. Six (10% of evaluable patients) reported no benefit.

Discussion: Evaluable patients in an opioid refractory class had a 91% major response rateto lidocaine. Overall, lidocaine was well tolerated. Approximately 30% of evaluable patientsreported some adverse event; the most common being lethargy. However, the effect was notclearly related to lidocaine.

Conclusion: Parenteral lidocaine appears to be rapidly effective for opioid refractory painand is well tolerated. A randomized controlled trial is needed to confirm these impressivebut preliminary uncontrolled results.

INTRODUCTION

PAIN IS ONE OF THE MOST PREVALENT symptomsamong patients with advanced cancer and

other illnesses that are cared for by hospice pro-grams.1 Of cancer patients, 40%–60% have painduring the course of their illness. This increasesto 60%–80% in advanced stages.2 In addition topain’s negative impact, unrelieved pain is linkedto depression and precludes patients from deal-ing with other important life issues they may

wish to address.3,4 The World Health Organiza-tion three-step hierarchy for pain managementhas been demonstrated to be effective in control-ling cancer pain in 70%–90% of patients.5 How-ever, 10%–30% continue to suffer from severepain despite high dose opioids.6

Pain that persists despite high-dose opioids hasbeen called opioid-refractory pain. For the pur-poses of research, one working definition of opi-oid-refractory pain is pain that persists despite200 mg or more of oral morphine equivalent per

San Diego Hospice and Palliative Care, San Diego, California.

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day. The causes of opioid-refractory pain are mul-tifactorial. Patients may suffer from a variety ofunderlying pain pathophysiologies.

Clinically, the broad categories of nociceptiveand neuropathic have been used to characterizepain pathophysiology and guide therapeutic ap-proaches. Nociceptive pain is the transduction ofnoxious thermal, chemical, or mechanical stimulithrough normal nerves. Neuropathic pain resultsfrom abnormal nerve function. This may be eitherbecause of a primary lesion in the nerve (such asa transection) or abnormal function of the nerve(such as in chemotherapy-induced pain). Painmay be spontaneous (without external stimulus)and described with terms such as “burning,”“shooting,” “radiating,” or “electric,” and be as-sociated with physical findings of hyperalgesia(reduced threshold for pain for a noxious stimu-lus) and allodynia (pain from a normally non-noxious stimulus). At the experimental level, thedifference between nociceptive pain and neuro-pathic pain begins to blur. For example, animaland human studies have shown that peripheralnoxious stimuli such as repetitive pressure orsubcutaneous injection of capsaicin lead to a phe-nomenon called windup, a form of central sensi-tization with neuropathic pain components. Inwindup, the peripheral noxious stimulus leads tochanges at the spinal cord level causing sec-ondary hyperalgesia and allodynia in the pe-riphery.

Currently, opioid-refractory pain is treatedwith adjunctive pain medications administered inaddition to opioids. Frequently used agents aretricyclic antidepressants and anti-epileptics.None of these act quickly. Most require days toweeks to have an effect.

Interventional approaches are sometimes usedfor opioid-refractory pain. Intraspinal (epiduralor intrathecal) delivery of medications may helpin a subset of these cases. For severe pain, a com-bination of an opioid, an �-2 agonist, and a so-dium channel-blocking agent are often infused.Also, peripheral nerve blocks or neurolysis havebeen used. However, these interventions are in-vasive and require subspecialty skills limitingtheir availability and appeal to patients.

Controlled sedation may quickly relieve painby rendering a patient unconscious. However,this robs a patient of the ability to interact. In ad-dition, its ethical use is reserved only when alltherapeutic options have been exhausted.

Thus, there is a significant population of pa-

tients whose pain is not relieved by contempo-rary approaches. Their pain may be severeenough that they cannot tolerate the pain whilesequential trials of partially effective adjuvantanalgesics are titrated over weeks to months. Or,they may not live long enough for these medica-tions to become effective. Requests for physicianassisted suicide or euthanasia can seem like a ra-tional response to such unrelieved pain.7 Thereexists a need for a widely available, acute inter-vention to quickly control severe neuropathic oropioid-refractory pain. There is a particularlycompelling need to develop a drug that relievesthe pain of a patient who is urgently admitted tothe hospital with “pain out of control” that per-sists after aggressive titration of parenteral opi-oids.

Intravenous lidocaine may be such an agent. Ithas been principally studied in patients with non-malignant pain who were otherwise healthy.Randomized, double-blind placebo studies haveshown that intravenous lidocaine can signifi-cantly reduce postherpetic neuralgia8,9 and dia-betic neuropathy pain10,11 compared with saline.It was introduced to San Diego Hospice as atranslation of this clinical research. Case reportsof lidocaine’s efficacy in cancer pain have beenpublished but there exist no randomized con-trolled trials in this population.12–14

In our institution, we have used parenteral li-docaine to treat patients admitted to an acute in-patient hospice unit who had persistent pain thatwas severe enough to require admission. After itsintroduction, there was a broadly held clinicalperception that parenteral lidocaine was useful inthe majority of patients treated. Six cases havebeen described where continuous parenteral li-docaine infusions, initiated in an inpatient settingand continued at home, provided rapid and sus-tained relief from severe intractable neuropathicand mixed neuropathic-nociceptive pain states.14

To assess parenteral lidocaine’s efficacy and tol-erability further, we undertook this retrospectivechart analysis.

METHODS

After institutional review board approval, 768consecutive charts of patients admitted to the In-patient Care Center of San Diego Hospice & Pal-liative Care during a period in 1999 were ob-tained from the medical records department. All

INTRAVENOUS LIDOCAINE AND SEVERE PAIN 661

charts were screened to see if parenteral lidocainewas ordered for the management of pain. Wherelidocaine was ordered, the chart was abstractedusing a standard data collection instrument.Table 1 lists the information that was abstracted.Specific pain descriptors abstracted includedwhether the pain was sharp, dull, radiating, burn-ing, crampy, throbbing, paroxysmal, or was as-sociated with paresthesias. Whether allodyniawas present on examination was also noted. Datawere collected in such a way that the patientcould not be identified.

The typical lidocaine dosing consisted of an in-travenous bolus of approximately 1–2 mg/kgover 15–20 minutes. Thirty minutes postinfusion,pain was reassessed. If there was improvement,a continuous infusion of lidocaine at approxi-mately 1 mg/kg/per hour was initiated. A frac-tion of the patients had the lidocaine infusionstarted without a preceding bolus. In a subset ofpatients, steady-state lidocaine levels were ob-tained.

The primary study end point was the assess-ment of clinical benefit. Based on the informationin the chart, the abstractor categorized the pa-tients in one of three categories (1) a major painresponse, (2) partial benefit, or (3) no benefit. Ev-idence of clinical response was derived from in-dications of change in pain scores and/or verbaldescription.

A decrease in pain score of 3 or more points ona scale of 0–10 was deemed a major pain responsebased on the following. Farrar et at have shownthat a decrement of 2 points or 30% on the 11point numerical pain rating scale is clinically sig-nificant.15,16 We defined a major response as amove from severe pain to moderate or mild painor a move from moderate to mild pain. Typically,mild pain is considered 1–3 on a scale of 10, mod-

erate pain is considered 4–6 on a scale of 10, andsevere pain is considered 7–10 on a scale of 10. Achange in pain value of 3 is capable of moving apatient from one pain category to a lower cate-gory except when starting with a value of 10. Forexample, a patient with a pain rating of 7 with adecrement in pain value of 3 would have an endvalue of 4 and move from the subjective categoryof severe pain to the category of moderate pain.

Where pain scale ratings were not available,patient’s verbal descriptions documented by clin-icians were used to evaluate the pain response.For example, “no pain” was used as evidence ofcomplete response and the equivalent of a 0 painrating. Descriptors such as “much better” ormovement from “moderate” to “mild” pain wereevidence of a major response. Statements such as“might be a little better” were evidence of a par-tial response. Patients who were cognitively im-paired were deemed unevaluable.

Data were entered into FileMaker Pro databasesoftware for cataloging and analysis.

RESULTS

Eighty-two patients received lidocaine. Onepatient, not in pain at baseline, was excludedfrom analysis. In this patient, parenteral lidocainewas used to substitute for oral gabapentin whenthe patient became unable to take oral medica-tions. One patient was excluded because the chartdid not contain enough information to evaluatelidocaine’s effect. Two patients received opioidsconcomitantly with parenteral lidocaine in amanner that precluded an analysis of lidocaine’sefficacy. Seventeen patients were not cognitivelyintact enough to describe the effects of lidocaineon their pain. Thus, overall 21 patients were un-evaluable. The remaining 61 patients were evalu-able and subjected to further analysis. Sixty-fourpercent of the evaluable patients were women;36% were men. The median age was 69 with arange from 21 to 88 years old.

Pain descriptors being abstracted were avail-able in 69% of evaluable patients’ charts. Whenpain descriptors were available, 78% of evaluablepatients had findings consistent with neuropathicpain (i.e., pain was described as radiating, burn-ing, associated with paresthesias, or allodyniawas present).

The median daily oral morphine equivalent dosethat patients were taking prior to the lidocaine chal-

THOMAS ET AL.662

TABLE 1. DATA ABSTRACTED DURING THE CHART REVIEW

Medical record numberAgeGenderCardiac historyMajor diagnosisPain descriptionMedications prior to lidocainePain response to lidocaine (complete/major, partial,

no benefit)Lidocaine serum levelDisposition (died/discharged)

lenge was 240 mg (range, 0–42,240 mg/d). Forty(66% of evaluable patients) were on at least one ad-junctive pain medicine in addition to opioids (non-steroidal anti-inflammatory drugs [NSAIDs], 39%;antiseizure medications, 30%; glucocorticoids, 28%;tricyclic antidepressants, 3%).

Five evaluable patients did not receive a lido-caine bolus, but rather were started on a continu-ous infusion. Pain was assessed once steady statelevels of lidocaine were attained. Fifty-six patientsdid receive a lidocaine bolus. In these patients, painresponse was assessed thirty minutes after initia-tion of the bolus. If there was a significant reduc-tion in pain at this time point, the lidocaine infu-sion was continued. Steady-state serum lidocainelevels were obtained in approximately half of thepatients. The average lidocaine level was 5.1 mg/Lwith a standard deviation of 2.9.

Opioids were at steady state levels prior to thelidocaine challenge in 56% of evaluable patients.However, in 44% of the evaluable patients, opi-oids were changed concurrently with the lido-caine challenge.

Based on patients’ report, 50 (82%) had majorrelief of their pain; 5 (8%) had a partial response;6 (10%) showed no benefit. As a subset of thosewith a major response, 44% of evaluable patientsreported complete resolution of their pain as ev-idenced by a pain rating of 0 or a verbal reportof “no pain.” (Fig. 1). Of the 50 patients with amajor response, quantitative data on pain ratings

before and after lidocaine was available for 24.The differential ranged from 3 to 10 points. Themedian pain rating differential was 7 points, withan average pain differential of 6.8, and a standarddeviation of 2.2.

Moreover, it is interesting to analyze two sub-sets of patients. First, of evaluable patients whohad findings consistent with neuropathic pain bydescription or examination, 82% had a major re-sponse, 9% had a partial response, and 9% re-ported no benefit. These findings closely parallelthose of the entire evaluable population. Second,a subset that met a working definition of opioid-refractory pain was evaluated (32 patients). Thispopulation has been empirically defined as thosewho still have pain despite an oral morphineequivalent dose 200 mg/d or more. Using thisdefinition, opioid-refractory patients had a 91%rate of major response.

In terms of safety, 30% of patients were notedto have some adverse effect, but only 3% of allpatients had the lidocaine infusion discontinuedbecause of the perceived adverse effect; 78% ofthe adverse effects were lethargy or somnolence.

No significant adverse effects were clearly at-tributable to lidocaine. Twenty-six percent of pa-tients had a known cardiac history such as coro-nary artery disease, congestive heart failure, oratrial fibrillation. No one had known active car-diac ischemia at the time of dosing. One patienthad a sudden death.

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90

80

70

60

50

40Per

cent

30

20

10

Major0

38

PartialResponse

Lidocaine Response

8

No Benefit

10

44

FIG. 1. Response of pain to parenteral lidocaine. Major, partial, and no benefit responses are shown. In a subset ofpatients, quantitative pain response data could be abstracted before and after lidocaine dosing. The fraction of majorresponders who could be determined to have a complete pain response is shown in darker grey (44%).

DISCUSSION

This chart review provides evidence that par-enteral lidocaine is well tolerated and could re-lieve opioid-refractory pain. Opioid-refractorypatients had a 91% rate of major response. Al-though this analysis is subject to all the inherentproblems of a retrospective, qualitative analysis,the potential efficacy of parenteral lidocaine foropioid-refractory pain remains impressive.

One potential problem with analysis is the con-current change in opioid dosing at the time of li-docaine initiation in a subset of patients. Opioidswere at steady state levels prior to the lidocainechallenge in 56% of evaluable patients. In thiscontext, changes in pain level after lidocaine dos-ing were likely attributable to lidocaine. How-ever, in 44% of the evaluable patients, opioidswere changed concurrently with the lidocainechallenge. The change reflected either a changein route of administration of an opioid or an opi-oid rotation to a new agent. In general, thesechanges were roughly equianalgesic (i.e., the oralmorphine equivalent dose before and after thechange was reasonably similar). Given changesin opioid dosing or in some cases the effect of in-complete cross-tolerance between opioids, theremay have been as much as a twofold effective dif-ference in opioid dose. However, even given thispotential opioid difference, it would take time forsteady state levels to be reached. The effects ofparenteral lidocaine given concurrently can beseen in thirty minutes. Therefore, even in this con-text, a successful pain response, temporally cor-related (within 30 minutes) with the initiation ofchanged opioids and lidocaine, is still most likelyrelated to lidocaine. In one case, bolus dosing oforal transmucosal fentanyl was given. Sufficienttime was given after the fentanyl boluses to havehad peak effects in the serum and yet the patientremained in severe pain. Again, in this context,although steady state opioid levels had not beenreached, an effect 30 minutes after lidocaine in-fusion is likely attributable to lidocaine.

Lidocaine is an amide local anesthetic that is anonselective sodium channel blocker. More than 10distinct human sodium channels have been identi-fied.17 Preliminary work has implicated subsets ofthese sodium channels to be responsible for painsensation.18–22 Antiepileptic agents may be anal-gesic, in part, because of sodium-channel blockingactivity. However, there exist no clinically availableselective sodium channel blocking agents.

In experimental animal pain models, par-enteral lidocaine decreases pain behaviors asso-ciated with hyperalgesia and allodynia–parame-ters associated with neuropathic pain and opioidrefractory pain.23–26 Further studies have foundevidence of spontaneously active sodium chan-nels in these experimental animal pain models.These abnormally firing sodium channels existalong injured nerves, at neuromas, and at the dor-sal root ganglion.24,27–30 Interestingly, lidocainehas been shown to suppress this ectopic, sponta-neous firing at concentrations that do not affectnormal nerve conduction.31 This data partiallyexplains lidocaine’s efficacy, but is insufficient toexplain all the phenomena associated with lido-caine. Ectopically firing sodium channels may ex-plain the clinical phenomenon of spontaneouspain, but it is not clear how it explains continu-ous phenomena such as allodynia. Thus, there arelikely to be other molecular mechanisms mediat-ing lidocaine’s pain relief.

Studies in humans show sodium channel ac-cumulation in injured nerves.32 There is also sub-stantial evidence that lidocaine can reduce ex-perimentally induced hyperalgesia and allodyniain humans.33–35 Moreover, there is case report ev-idence that lidocaine is efficacious clinically in pa-tients with pain syndromes,36 in addition to theclinical trials previously discussed.8–11

A survey of studies conducted in humans re-veals that lidocaine boluses ranging from 1–5mg/kg have been effective. No significant ad-verse effects have been reported when thesedoses are used. A similar survey of the literaturereveals time until pain relief ranges from 1 to 45minutes. Ferrante et al.37 studied the effect of li-docaine’s concentration on neuropathic pain re-lief. Their data shows that the lidocaine concen-tration at the time of complete pain relief was 3.79mg/L � 1.00.37 This concentration is within therange of lidocaine concentration that is consid-ered clinically safe (up to 5 mg/L) and is consis-tent with the steady-state levels that were moni-tored in this chart review. The literature indicatesthat muscle twitching begins at about 8 mg/L andseizures may occur over 10 mg/L. Serious car-diac toxicity occurs only with levels greater than25 mg/L.38 In presumed clinically safe concen-trations, lidocaine’s ability to suppress ventricu-lar arrhythmias in the aftermath of an acute myo-cardial infarction has been studied. An analysisof 14 randomized studies showed that the oddsof early death were one third greater in those who

THOMAS ET AL.664

had received lidocaine, although this result wasnot statistically significant.39 However, this ob-servation raises the formal concern that lidocainecould do harm. The magnitude of risk and whomay be at risk is unknown.

In this chart review, lidocaine appeared to bewell tolerated despite the fact that 26% hadunderlying cardiac disease. Thirty percent of pa-tients were noted to have some adverse effect, butno serious adverse effect was clearly related to li-docaine. The most common adverse effects werelethargy or somnolence. These effects are knownpotential side effects of lidocaine. However, it hasbeen empirically observed that when an effectiveadjunctive agent is added to high-dose opioids,the improvement in pain may leave the patientwith a relative excess of opioids that can lead tosomnolence. Often, the opioid level needs to bedecreased. This phenomenon was observed dur-ing this retrospective analysis but due to its lim-itations could not be quantified. Interestingly, al-though, of those who reported lethargy orsomnolence, 94% had some pain relief with lido-caine. Additionally, patients in severe pain are of-ten sleep-deprived. Once good pain control is es-tablished, somnolence may be an attempt torectify the sleep deprivation. Thus, it is not clearif the lethargy and somnolence noted after the li-docaine infusion are a direct side effect of themedication or a consequence of its efficacy in painrelief.

Although one patient had a sudden death, in ahospice population no death can be characterizedas unexpected. This patient was an 87-year-oldwoman with no known cardiac disease except hy-pertension. However, she was known to have adeep vein thrombosis and theoretically couldhave had a pulmonary embolus. Nevertheless,given lidocaine’s potential for cardiac toxicity, li-docaine must be considered as a possible con-tributing factor. Unfortunately, no lidocaine levelinformation was available for this patient and noautopsy was performed.

Overall, the death and discharge rates for pa-tients who received lidocaine were consistentwith the inpatient population in general. Of thepatients who received lidocaine, 73% died duringtheir inpatient stay, and 27% were dischargedalive. These rates are the same as for the morethan 1500 patients who are admitted to the facil-ity each year.

Thus, although lidocaine has molecular, ex-perimental, and clinical evidence of efficacy in

non-cancer–pain relief and a track record of over-all safety in clinical trials, there are no controlledtrials in neuropathic or opioid-refractory pain toguide therapy in end-of-life care. The hospice andpalliative care population is often frail, elderly,and has frequent cardiac comorbidity. The prac-tical result is that intravenous lidocaine is not inwidespread clinical use.

Therefore, we performed this retrospectivechart review to as a preliminary step to supportthe need for further study. We interpret these pre-liminary results to suggest that intravenous lido-caine may be a safe and effective agent for theacute management of opioid-refractory pain.There is clearly a need for better study.

If the hypothesis that lidocaine relieves opioid-refractory pain quickly and effectively is correct,this could alter the clinical practice in the care ofthe 50,000–150,000 patients with cancer with opi-oid refractory cancer pain who die in the UnitedStates each year. For most patients, this acute painrelief could provide a therapeutic window whenother adjunctive pain medications can be startedand titrated to effective doses before discharge.Lidocaine could be administered in the emer-gency department and on hospital units in the ab-sence of continuous cardiac monitoring. This maydecrease admissions or length of stay for opioid-refractory pain crises. Moreover, our experiencesuggests this clinical intervention can be pro-vided safely in the home where the bulk of hos-pice care is delivered. However, further testingthis hypothesis will require a prospective, ran-domized, placebo-controlled trial to establish li-docaine’s efficacy and safety in order to make itwidely available.

ACKNOWLEDGMENTS

We would like to thank the numerous clini-cians who were involved in treating patients withintravenous lidocaine over the period of this chartreview. In particular, Rebecca Ferrini, M.D.,Frances Philley, M.D., Charles Lewis, M.D., andMichael Frederich, M.D. were instrumental asclinician leaders. We also appreciate the supportof the nurses and other staff of San Diego Hos-pice for caring for these challenging patients andfamilies. Drug therapy is but only one part of re-lieving severe pain. This research project wasmade possible in part by a grant from the Vista-Care Hospice Foundation. This project received

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the approval of the San Diego Hospice Institu-tional Review Board.

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Address reprint requests to:Jay Thomas, M.D., Ph.D.

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