Puin, 45 (1991) 145-148 0 1991 Elsevier Science Publishers ADONIS
145 B.V. 0304-3959/81/$03.50
0304395991001177
PAIN 01840
Clinical Note
Subcutaneous lidocaine for treatment of neuropathic cancer pain William
G. Brose
a and Micheal
J. Cousins
b
’ Pain Management Service, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA (U.S.A.), and h Department of Anaesthesia and Pain Management, Royal North Shore Hospital, St. Leonards, NS W (Australia) (Received
6 November
1990, revision received
18 January
1991, accepted
21 January
1991)
Three patients with terminal malignancy reporting ineffective analgesia using systemic and subseSummary quently spinal opiates were treated with subcutaneous infusion of 10% lidocaine hydrochloride. During the infusion, reasonably stable blood concentrations were achieved and maintained using a subcutaneous infusion at varying dose rates over days to months with improvement of the pain complaints which continued to be refractory to conventional analgesics. Blood lidocaine levels obtained at regular intervals revealed effective concentrations between 2 and 5 pgg/ml for each patient. Key words:
Lidocaine;
Subcutaneous
infusion;
Neuropathic
Introduction Terminal cancer is frequently complicated by pain. Using the World Health Organization ‘analgesic ladder’ for management of cancer pain over 90% of patients can be relieved. A combination of strong opiates, nonsteroidal medications, acetaminophen, and other oral adjuvant medications is commonly employed. Other alternative opiate administration systems have been proposed for those patients who do not receive adequate relief using the analgesic ladder. These include subcutaneous opiate infusions and spinal opiates. However, even when these progressive measures are employed to treat cancer pain, some patients continue to experience uncontrolled pain. Patients with proven direct neural invasion by tumor often fall into this later unfavorable category. The quality of pain described by these patients is typically burning, electrical, occasionally lancinating, with associated dysesthesias and often allodynia. The pain is frequently accompanied by autonomic and occasionally motor changes depending on the neural structure compromised. These symptoms and findings confirm a diagnosis of neuropathic pain [lo]. This case series reports
Correspondence to: William G. Brose, M.D., Pain Management Service, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, U.S.A.
pain
on 3 cases with neuropathic pain who failed the analgesic ladder. In these patients analgesic therapy progressed to subcutaneous infusion plus adjuvants and finally spinal opiates combined with adjuvants, all with ineffective pain relief. In an effort to discover a useful analgesic regimen for managing each of these patients, a doubleblind infusion scheme was utilized which was placebo controlled. This infusion scheme was designed so that each of 3 infusions were delivered in a randomized fashion intravenously over 30 min. Serial visual analog pain (VAPS) and sedation (VASS) scores were obtained every 5 min throughout the study period. An analgesic response was arbitrarily defined as a change of 20% or more in the VAPS. If an analgesic response was seen with the infusion, the next infusion was delayed until the VAPS had returned within 20% of baseline. In each case the success of the intravenous lidocaine prompted a trial of subcutaneous lidocaine delivered via continuous infusion with excellent results in all 3 patients.
Case report Case I A 58-year-old white male with Pancoast tumor who presented with radiographically (CT scan) demonstrated invasion of the posterior cord of the bra&al plexus and complaints of continuous severe burning arm pain. The pain was in the distribution of the radial
146
nerve initially, with dysesthesiae and lancinating pain felt throughout the arm. He also demonstrated weakness of the triceps and wrist flexors. At the time of the intravenous lidocaine trial he had been maintained on 40 mg epidural morphine 3 times daily. in addition to indomethacin 500 mg b.i.d., and amitriptyline 25 mg each night. Trials of oral carbamazepine (1200 mg/day) and clonazepam (3 mg/day) had been ineffective. The patient received randomized blinded infusions of opiate (fentanyl 500 pg). lidocaine (4 mg/kg) or an equal volume of normal saline each over 30 min. Sequential visual analog pain scores (VAPS) revealed an analgesic response to the lidocaine (initial VAPS = 80,000, final VAPS = 23/100) little placebo response (initial VAPS = 71, final VAPS = 64), while the opiate provided sedation without significant analgesia (initial VAPS = 64, final VAPS = 62). Given the patient’s favorable response to systemically administered lidocaine, the patient was offered a trial of subcutaneous lidocaine infusion. The trial was initiated with baseline measurement of pain (VAPS = 63/100), sedation (VASS = 32/100), BP, pulse, and area of topical anesthesia recorded. Lidocaine was administered in doses ranging from 100 to 160 mg/h (1.0.-1.6 ml/h) for the next 500 h with intermittent sampling of blood and recording of vital signs, local area of anesthesia, pain and sedation. The patient reported good analgesia and minimal sedation during the 5 weeks. Interval episodes of recurrent pain were associated with technical problems of lidocaine delivery (pump malfunction, needle displacement). The measured blood concentrations remained between 1.5 and 2.5 p&/ml with a trend toward increasing blood concentration as treatment continued. The patient demonstrated no signs of CNS, cardiac or local tissue toxicity from the lidocaine administration during the treatment period. The patient died of tumor-related causes 45 days into the treatment. Case ? A 62-year-old white female with widely metastatic small cell carcinoma of the lung. The patient presented to the Pain Management Unit shortly following her diagnosis of lung cancer. She initially described hip and leg pain on the left side with bone scan and X-ray evidence of metastatic disease. Her initial management consisted of oral methadone and indomethacin. She was maintains on this therapy requiring increasing opiate dosing over several weeks. Failure of subcutaneous morphine infusion due to development of unwanted sedation prompted a trial of spinal opiates. Adjuvant therapy including tricyclic antidepressants, NSAIDs, carbamazepine, mexiletine, baclofen and clonazepam all at increasing doses was unsuccessful. After increasing doses of subarachnoid morphine (50 mg/day) failed to provide relief, repeat imaging was performed. A CT
scan revealed tumor infiltration of the L2 neural foramen, surgical decompression was attempted but operative findings included direct neural invasion of the L2 root by tumor. External beam radiotherapy failed to resolve the pain during a subsequent treatment period and the patient also developed quadriceps weakness. The patient was hospitalized for terminal care with high dose intravenous morphine. Prior to the initiatio~l of the intravenous morphine, the patient received randomized blinded infusions of opiate (fentanyl 500 pg), lidocaine (4 mg/kg) or an equal volume of normal saline each over 30 min. The patient reported marked improvement in her pain on the intravenous lidocaine (initial VAPS = 92/100, final VAPS = 12/100). Ten percent lidocaine infusion was initiated subcutaneously at 100 mg/h (1 ml/h). The dose administered was adjusted (loo-150 mg/h) to optimize analgesia over the next 2 days. Blood lidocaine levels from 4 to 5 pg/ml were maintained with a dose of 150 mg/h. Subcutaneous lidocaine was used in conjunction with subarachnoid morphine (50100 mg/day), indomethacin, and amitriptyline to maintain analgesia. Lidocaine concentrations were measured intermittently over the ensuing several weeks. During the treatment period several episodes of recurrent pain were correlated with blood lidocaine concentrations below 2 pgfml. These episodes responded to dose adjustment. The patient continued on the combined systemic lidocaine and spinal opiate regimen for an additional 6 months when she died of complications to her tumor. Case 3 A .57-year-old white male with adenocarcinoma of the colon who presented with abdominal pain and small bowel obstruction. He had a previous history of Dukes C adenocarcinoma surgically treated 12 months earlier. Medical management of the bowel obstruction failed and the patient was taken for surgical decompression. During the surgical procedure the tumor invasion of the lumbar somatic plexus was suspected. Postoperative pain was unresponsive to systemic opiates and the patient developed frank hallucinations. Epidural morphine provided improved but incomplete pain relief. The patient continued to have nausea and vomiting with partial bowel obstruction. The patient received randomized blinded infusions of opiate (fentanyl 300 pg), lidocaine (4 mg/kg) or an equal volume of normal saline each over 30 min. The double-blind infusion demonstrated profound reproducible analgesia with lidocaine (initial VAPS = 65/100, final VAPS = O/100) and minimal effect from placebo (initial VAPS = 60/100, final VAPS = 53) or opiate (initial VAPS = 53/100, final VAPS = 67/100). The blood lidocaine concentration measured when the patient first described analgesia was 2.3 pg/ml. Subcutaneous lidocaine was initiated at 100 mg/h. Four hours later the patient reported a return of pain. The lidocaine blood level at this time was 1.3 pgg/ml. The
147
dose was increased to 120 mg/h to maintain a blood lidocaine concentration of > 2 pg/ml. The patient was discharged on combined spinal opiate and subcutaneous lidocaine with intermittent monitoring of lidoCaine concentration. The lidocaine infusion was maintained at 120 mg/h for the next 3 weeks until the patient’s death.
Discussion The majority of pain reported by patients suffering with cancer is thought to be nociceptive. Nociceptive pain is due to the discharge of selective A6 and C fibers (nociceptors). This pain is typically responsive to opiates and NSAIDs. A small subset of cancer patients may also develop pain which is due to functional abnormality of the nerves usually by tumor invasion or compression, this latter type of pain is termed neuropathic. Neuropathic pain is typically not responsive to systemic opiate therapy 111.Analgesic adjuvants, such as tricyclic antidepressants and anticonvulsants, have been utilized to control neuropatbic pain in these patients [29]. Membrane stabilizers such as flecainide, tocainide, and mexiletine have also been reported to have analgesic properties [10,12,21]. Lidocaine also provides analgesia in certain pain states that would be characterized as neuropathic [3,10,13,19,20,24,25]. The systemic administration of local anesthetics has been reported to provide effects which are not explained by conduction blockade. Local anesthetics provide anticonvulsant action [2], as well as decreasing the coughing reflex and treating laryngospasm [15,27]. Local anesthetics block action potential conduction when applied directly to neural tissue [22,26]. This blockade is secondary to the ability of local anesthetics to modify sodium channels within the nerve cell membrane 141.Lidocaine blockade of sodium channels is frequency and voltage dependent [5,18]. Because of these properties, lidocaine may be able to target spontaneously active nerves while not effecting conduction in normal nerves. Lidocaine by blocking sodium channels appears to suppress spontaneous injury and neuroma discharge in AS and C fibers [6]. Local anesthetics have also been reported to modify other functional properties of the neuronal membrane in addition to producing axonal blockade. Prolongation of the refractory period of nerves is one such example (71. This dampening of membrane recovery is manifested by the inhibition of high frequency activity in the axon [7]. In vitro experiments supporting the analgesic activity of systemically administered local anesthetics suggest that lidocaine in particular decreases spinal cord monosynapti~ and polysynaptic reflexes [28,29]. These electrophysiologic properties of lidocaine may account for the analgesic effect seen in these patients.
Subcutaneous administration of lidocaine, using an ambulatory infusion pump, represents a new delivery route to ad~nister lidocaine systemically. Subcutaneous delivery of opiates has established utility in pain management. Relatively stable blood concentrations and ease of maintaining access are advantages of this technique for opiate delivery. Concentrated lidocaine (10%) has been been reported to cause muscle irritation and necrosis when injected intramuscularly (Xylocard package insert). There are no toxicity data available on the continuous subcutaneous administration of concentrated lidocaine solutions. In these 3 patients there were no signs of developing local toxicity. This was despite the long treatment times (3 weeks, 6 weeks and 6 months) in these patients. Furthermore, the size of the anesthetic area induced by the infusions was small in all patients so that concern for self-injury to the anesthetic area proved to be slight. Systemic toxicity represents another risk from the subcutaneous ad~nistration of lidocaine. Neuroto~city is thought to occur at plasma levels between 10 and 15 pg/ml [8]. Fortunately lidocaine causes CNS excitation rather than depression as toxicity approaches. CNS changes associated with progressively increasing serum concentrations are li~theadedness, circumoral numbness, dizziness, tinnitus, visual changes, garbled speech, dysarthria, periodic muscle spasm and subsequently frank convulsions [8,9]. These predictable symptoms may provide a safe guard against further CNS toxicity by providing a warning to patients that the infusion needs to be terminated. Experience with the use of prolonged continuous intravenous infusion of lidocaine for treatment of ventricular dysrhythmia has identified problems that may occur in patients with cardiac disease [9,17,23]. These problems include marked alteration in clearance associated with congestive failure 1171, and increasing age [23]. flowever, some patients develop lidocaine toxicity without manifestation of disease known to alter metabolism [9]. In addition to changes in metabolism of the parent drug, accumulation of monoethylglycinexylidide (MEGX), an active lidocaine metabolite, has also been associated with toxicity [9,11,17,23]. With prolonged administration of lidocaine in healthy subjects, declining clearance of lidocaine and accumulation of MEGX with prolonged administration has also been reported. The extraction technique and column conditions utilized for our CC assay of lidocaine did not allow accurate quantification of MEGX, therefore these levels are not reported in our patients. Appropriate assay conditions have been described elsewhere (161. Increasing lidocaine blood concentrations with prolonged administration was seen in 2 of the 3 patients reported, suggesting that decreased clearance had developed. The recognized problems of prolonged intravenous
14X
lidocaioe administration presented from the cardiac literature suggest that caution should be employed in utilizing subcutaneous lidocaine therapy for pain. The narrow therapeutic range of systemic lidocaine for analgesia seen in the patients presented here supports the need for regular monitoring of lidocaine and MECiX concentrations in the blood. This requirement for regular drug monito~ng is Iikely to be increasingIy important in patients with terminal cancer who often have marked metabolic derangement associated with their disease. With the appropriate monitoring, prolonged continuous subcutaneous Iidocaine therapy may be useful. The analgesia obtained in these 3 refractory patients suggests the possible clinical utility of subcutaneous lidocaine in managing patients with refractory neuropathic cancer pain. Further randomized controlled trials of lidocaine in such patients is necessary to establish such utility. In addition, pharmacokinetic studies of subcutaneous lidocaine should be accomplished to establish bioavailability and distribution kinetics so that safe drug dosing and monitoring guidelines can be established.
References 1 ArnPr, S. and Meyerson, B.A., Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain, Pain, 33 (1988) Il. 2 Bernhard, C.G. and Bohm, E., Local Anaesthetics as Anticonvulsants, Almquist and Wiskell, Uppsala, 1965. 3 Boas. R.A.. Covino, B.G. and Shahnarian, A., Analgesic responses to IV lignocaine, Br. J. Anaesth., 54 (1982) 501. 4 Cahalan, M.D.. Local anaesthetic block of sodium channels in normal and pronase-treated squid giant axons, Biophys. J., 23 (1978) 285. 5 Catterall, W.A., Common modes of drug action on Nai channels: local anesthetics, antiarrhythmics and anticonvulsants, Trends Pharm. Sci., 8 (1987) 57. 6 Chahal, C.. Russell, L.C. and Burchiel, K.J., The effect of Intravenous lidocaine, tocainide, and mexiletine on spontaneously active fibers originating in rat sciatic neuromas, Pain, 38 (1989) 333. 7 Condouris, G.A., Local anesthetics as modulators of neural information. In: J.J. Bonica and D. Albe-Fessard (Eds.), Advances in Pain Research and Therapy, Vol. 1, Raven Press, New York, 1976. of local anesthetic agents. In: 8 Covino, B.C., Clinical pharmacology M.J. Cousins and P.O. Bridenbaugh (Eds.), Neural Blockade in Clinical Anesthesia and Management of Pain, 2nd Edn., Lippincott, Philadelphia, PA, 1988, Ch. 4. R., Parker, M. and Atkinson, A.J., Excessive serum 9 Davison, lidocaine levels during maintenance infusions: m~han~sms and prevention, Am. Heart J., 104 (1982) 203. 10 Dejard. A.. Petersen, P. and Kastrup, J., Mexiletine for the treatment of chronic painful diabetic neuropathy, Lancet, i (1988) 9. D.E., Loremo. B.. Werns, S. and Reidenberg, M.M., 11 Drayer.
Plasma levels. protem bindmg, and elimination data of lidocarnt~ and acttve metaboltter tn cardiac pattents of vartous ages. Clru Pharmacol. Ther.. 34 (1983) 14. 12 Dunlop, R.. Davies. R.J., Hockley. J. and Turner, P.. Analgesrc effects of oraf flecanide (Letter), Lancet. i (198X) 42.0. 13 Edwards, W.T.. Hahtb. F.. Burney. R.G. and Begm.
145 B.V. 0304-3959/81/$03.50
0304395991001177
PAIN 01840
Clinical Note
Subcutaneous lidocaine for treatment of neuropathic cancer pain William
G. Brose
a and Micheal
J. Cousins
b
’ Pain Management Service, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA (U.S.A.), and h Department of Anaesthesia and Pain Management, Royal North Shore Hospital, St. Leonards, NS W (Australia) (Received
6 November
1990, revision received
18 January
1991, accepted
21 January
1991)
Three patients with terminal malignancy reporting ineffective analgesia using systemic and subseSummary quently spinal opiates were treated with subcutaneous infusion of 10% lidocaine hydrochloride. During the infusion, reasonably stable blood concentrations were achieved and maintained using a subcutaneous infusion at varying dose rates over days to months with improvement of the pain complaints which continued to be refractory to conventional analgesics. Blood lidocaine levels obtained at regular intervals revealed effective concentrations between 2 and 5 pgg/ml for each patient. Key words:
Lidocaine;
Subcutaneous
infusion;
Neuropathic
Introduction Terminal cancer is frequently complicated by pain. Using the World Health Organization ‘analgesic ladder’ for management of cancer pain over 90% of patients can be relieved. A combination of strong opiates, nonsteroidal medications, acetaminophen, and other oral adjuvant medications is commonly employed. Other alternative opiate administration systems have been proposed for those patients who do not receive adequate relief using the analgesic ladder. These include subcutaneous opiate infusions and spinal opiates. However, even when these progressive measures are employed to treat cancer pain, some patients continue to experience uncontrolled pain. Patients with proven direct neural invasion by tumor often fall into this later unfavorable category. The quality of pain described by these patients is typically burning, electrical, occasionally lancinating, with associated dysesthesias and often allodynia. The pain is frequently accompanied by autonomic and occasionally motor changes depending on the neural structure compromised. These symptoms and findings confirm a diagnosis of neuropathic pain [lo]. This case series reports
Correspondence to: William G. Brose, M.D., Pain Management Service, Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, U.S.A.
pain
on 3 cases with neuropathic pain who failed the analgesic ladder. In these patients analgesic therapy progressed to subcutaneous infusion plus adjuvants and finally spinal opiates combined with adjuvants, all with ineffective pain relief. In an effort to discover a useful analgesic regimen for managing each of these patients, a doubleblind infusion scheme was utilized which was placebo controlled. This infusion scheme was designed so that each of 3 infusions were delivered in a randomized fashion intravenously over 30 min. Serial visual analog pain (VAPS) and sedation (VASS) scores were obtained every 5 min throughout the study period. An analgesic response was arbitrarily defined as a change of 20% or more in the VAPS. If an analgesic response was seen with the infusion, the next infusion was delayed until the VAPS had returned within 20% of baseline. In each case the success of the intravenous lidocaine prompted a trial of subcutaneous lidocaine delivered via continuous infusion with excellent results in all 3 patients.
Case report Case I A 58-year-old white male with Pancoast tumor who presented with radiographically (CT scan) demonstrated invasion of the posterior cord of the bra&al plexus and complaints of continuous severe burning arm pain. The pain was in the distribution of the radial
146
nerve initially, with dysesthesiae and lancinating pain felt throughout the arm. He also demonstrated weakness of the triceps and wrist flexors. At the time of the intravenous lidocaine trial he had been maintained on 40 mg epidural morphine 3 times daily. in addition to indomethacin 500 mg b.i.d., and amitriptyline 25 mg each night. Trials of oral carbamazepine (1200 mg/day) and clonazepam (3 mg/day) had been ineffective. The patient received randomized blinded infusions of opiate (fentanyl 500 pg). lidocaine (4 mg/kg) or an equal volume of normal saline each over 30 min. Sequential visual analog pain scores (VAPS) revealed an analgesic response to the lidocaine (initial VAPS = 80,000, final VAPS = 23/100) little placebo response (initial VAPS = 71, final VAPS = 64), while the opiate provided sedation without significant analgesia (initial VAPS = 64, final VAPS = 62). Given the patient’s favorable response to systemically administered lidocaine, the patient was offered a trial of subcutaneous lidocaine infusion. The trial was initiated with baseline measurement of pain (VAPS = 63/100), sedation (VASS = 32/100), BP, pulse, and area of topical anesthesia recorded. Lidocaine was administered in doses ranging from 100 to 160 mg/h (1.0.-1.6 ml/h) for the next 500 h with intermittent sampling of blood and recording of vital signs, local area of anesthesia, pain and sedation. The patient reported good analgesia and minimal sedation during the 5 weeks. Interval episodes of recurrent pain were associated with technical problems of lidocaine delivery (pump malfunction, needle displacement). The measured blood concentrations remained between 1.5 and 2.5 p&/ml with a trend toward increasing blood concentration as treatment continued. The patient demonstrated no signs of CNS, cardiac or local tissue toxicity from the lidocaine administration during the treatment period. The patient died of tumor-related causes 45 days into the treatment. Case ? A 62-year-old white female with widely metastatic small cell carcinoma of the lung. The patient presented to the Pain Management Unit shortly following her diagnosis of lung cancer. She initially described hip and leg pain on the left side with bone scan and X-ray evidence of metastatic disease. Her initial management consisted of oral methadone and indomethacin. She was maintains on this therapy requiring increasing opiate dosing over several weeks. Failure of subcutaneous morphine infusion due to development of unwanted sedation prompted a trial of spinal opiates. Adjuvant therapy including tricyclic antidepressants, NSAIDs, carbamazepine, mexiletine, baclofen and clonazepam all at increasing doses was unsuccessful. After increasing doses of subarachnoid morphine (50 mg/day) failed to provide relief, repeat imaging was performed. A CT
scan revealed tumor infiltration of the L2 neural foramen, surgical decompression was attempted but operative findings included direct neural invasion of the L2 root by tumor. External beam radiotherapy failed to resolve the pain during a subsequent treatment period and the patient also developed quadriceps weakness. The patient was hospitalized for terminal care with high dose intravenous morphine. Prior to the initiatio~l of the intravenous morphine, the patient received randomized blinded infusions of opiate (fentanyl 500 pg), lidocaine (4 mg/kg) or an equal volume of normal saline each over 30 min. The patient reported marked improvement in her pain on the intravenous lidocaine (initial VAPS = 92/100, final VAPS = 12/100). Ten percent lidocaine infusion was initiated subcutaneously at 100 mg/h (1 ml/h). The dose administered was adjusted (loo-150 mg/h) to optimize analgesia over the next 2 days. Blood lidocaine levels from 4 to 5 pg/ml were maintained with a dose of 150 mg/h. Subcutaneous lidocaine was used in conjunction with subarachnoid morphine (50100 mg/day), indomethacin, and amitriptyline to maintain analgesia. Lidocaine concentrations were measured intermittently over the ensuing several weeks. During the treatment period several episodes of recurrent pain were correlated with blood lidocaine concentrations below 2 pgfml. These episodes responded to dose adjustment. The patient continued on the combined systemic lidocaine and spinal opiate regimen for an additional 6 months when she died of complications to her tumor. Case 3 A .57-year-old white male with adenocarcinoma of the colon who presented with abdominal pain and small bowel obstruction. He had a previous history of Dukes C adenocarcinoma surgically treated 12 months earlier. Medical management of the bowel obstruction failed and the patient was taken for surgical decompression. During the surgical procedure the tumor invasion of the lumbar somatic plexus was suspected. Postoperative pain was unresponsive to systemic opiates and the patient developed frank hallucinations. Epidural morphine provided improved but incomplete pain relief. The patient continued to have nausea and vomiting with partial bowel obstruction. The patient received randomized blinded infusions of opiate (fentanyl 300 pg), lidocaine (4 mg/kg) or an equal volume of normal saline each over 30 min. The double-blind infusion demonstrated profound reproducible analgesia with lidocaine (initial VAPS = 65/100, final VAPS = O/100) and minimal effect from placebo (initial VAPS = 60/100, final VAPS = 53) or opiate (initial VAPS = 53/100, final VAPS = 67/100). The blood lidocaine concentration measured when the patient first described analgesia was 2.3 pg/ml. Subcutaneous lidocaine was initiated at 100 mg/h. Four hours later the patient reported a return of pain. The lidocaine blood level at this time was 1.3 pgg/ml. The
147
dose was increased to 120 mg/h to maintain a blood lidocaine concentration of > 2 pg/ml. The patient was discharged on combined spinal opiate and subcutaneous lidocaine with intermittent monitoring of lidoCaine concentration. The lidocaine infusion was maintained at 120 mg/h for the next 3 weeks until the patient’s death.
Discussion The majority of pain reported by patients suffering with cancer is thought to be nociceptive. Nociceptive pain is due to the discharge of selective A6 and C fibers (nociceptors). This pain is typically responsive to opiates and NSAIDs. A small subset of cancer patients may also develop pain which is due to functional abnormality of the nerves usually by tumor invasion or compression, this latter type of pain is termed neuropathic. Neuropathic pain is typically not responsive to systemic opiate therapy 111.Analgesic adjuvants, such as tricyclic antidepressants and anticonvulsants, have been utilized to control neuropatbic pain in these patients [29]. Membrane stabilizers such as flecainide, tocainide, and mexiletine have also been reported to have analgesic properties [10,12,21]. Lidocaine also provides analgesia in certain pain states that would be characterized as neuropathic [3,10,13,19,20,24,25]. The systemic administration of local anesthetics has been reported to provide effects which are not explained by conduction blockade. Local anesthetics provide anticonvulsant action [2], as well as decreasing the coughing reflex and treating laryngospasm [15,27]. Local anesthetics block action potential conduction when applied directly to neural tissue [22,26]. This blockade is secondary to the ability of local anesthetics to modify sodium channels within the nerve cell membrane 141.Lidocaine blockade of sodium channels is frequency and voltage dependent [5,18]. Because of these properties, lidocaine may be able to target spontaneously active nerves while not effecting conduction in normal nerves. Lidocaine by blocking sodium channels appears to suppress spontaneous injury and neuroma discharge in AS and C fibers [6]. Local anesthetics have also been reported to modify other functional properties of the neuronal membrane in addition to producing axonal blockade. Prolongation of the refractory period of nerves is one such example (71. This dampening of membrane recovery is manifested by the inhibition of high frequency activity in the axon [7]. In vitro experiments supporting the analgesic activity of systemically administered local anesthetics suggest that lidocaine in particular decreases spinal cord monosynapti~ and polysynaptic reflexes [28,29]. These electrophysiologic properties of lidocaine may account for the analgesic effect seen in these patients.
Subcutaneous administration of lidocaine, using an ambulatory infusion pump, represents a new delivery route to ad~nister lidocaine systemically. Subcutaneous delivery of opiates has established utility in pain management. Relatively stable blood concentrations and ease of maintaining access are advantages of this technique for opiate delivery. Concentrated lidocaine (10%) has been been reported to cause muscle irritation and necrosis when injected intramuscularly (Xylocard package insert). There are no toxicity data available on the continuous subcutaneous administration of concentrated lidocaine solutions. In these 3 patients there were no signs of developing local toxicity. This was despite the long treatment times (3 weeks, 6 weeks and 6 months) in these patients. Furthermore, the size of the anesthetic area induced by the infusions was small in all patients so that concern for self-injury to the anesthetic area proved to be slight. Systemic toxicity represents another risk from the subcutaneous ad~nistration of lidocaine. Neuroto~city is thought to occur at plasma levels between 10 and 15 pg/ml [8]. Fortunately lidocaine causes CNS excitation rather than depression as toxicity approaches. CNS changes associated with progressively increasing serum concentrations are li~theadedness, circumoral numbness, dizziness, tinnitus, visual changes, garbled speech, dysarthria, periodic muscle spasm and subsequently frank convulsions [8,9]. These predictable symptoms may provide a safe guard against further CNS toxicity by providing a warning to patients that the infusion needs to be terminated. Experience with the use of prolonged continuous intravenous infusion of lidocaine for treatment of ventricular dysrhythmia has identified problems that may occur in patients with cardiac disease [9,17,23]. These problems include marked alteration in clearance associated with congestive failure 1171, and increasing age [23]. flowever, some patients develop lidocaine toxicity without manifestation of disease known to alter metabolism [9]. In addition to changes in metabolism of the parent drug, accumulation of monoethylglycinexylidide (MEGX), an active lidocaine metabolite, has also been associated with toxicity [9,11,17,23]. With prolonged administration of lidocaine in healthy subjects, declining clearance of lidocaine and accumulation of MEGX with prolonged administration has also been reported. The extraction technique and column conditions utilized for our CC assay of lidocaine did not allow accurate quantification of MEGX, therefore these levels are not reported in our patients. Appropriate assay conditions have been described elsewhere (161. Increasing lidocaine blood concentrations with prolonged administration was seen in 2 of the 3 patients reported, suggesting that decreased clearance had developed. The recognized problems of prolonged intravenous
14X
lidocaioe administration presented from the cardiac literature suggest that caution should be employed in utilizing subcutaneous lidocaine therapy for pain. The narrow therapeutic range of systemic lidocaine for analgesia seen in the patients presented here supports the need for regular monitoring of lidocaine and MECiX concentrations in the blood. This requirement for regular drug monito~ng is Iikely to be increasingIy important in patients with terminal cancer who often have marked metabolic derangement associated with their disease. With the appropriate monitoring, prolonged continuous subcutaneous Iidocaine therapy may be useful. The analgesia obtained in these 3 refractory patients suggests the possible clinical utility of subcutaneous lidocaine in managing patients with refractory neuropathic cancer pain. Further randomized controlled trials of lidocaine in such patients is necessary to establish such utility. In addition, pharmacokinetic studies of subcutaneous lidocaine should be accomplished to establish bioavailability and distribution kinetics so that safe drug dosing and monitoring guidelines can be established.
References 1 ArnPr, S. and Meyerson, B.A., Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain, Pain, 33 (1988) Il. 2 Bernhard, C.G. and Bohm, E., Local Anaesthetics as Anticonvulsants, Almquist and Wiskell, Uppsala, 1965. 3 Boas. R.A.. Covino, B.G. and Shahnarian, A., Analgesic responses to IV lignocaine, Br. J. Anaesth., 54 (1982) 501. 4 Cahalan, M.D.. Local anaesthetic block of sodium channels in normal and pronase-treated squid giant axons, Biophys. J., 23 (1978) 285. 5 Catterall, W.A., Common modes of drug action on Nai channels: local anesthetics, antiarrhythmics and anticonvulsants, Trends Pharm. Sci., 8 (1987) 57. 6 Chahal, C.. Russell, L.C. and Burchiel, K.J., The effect of Intravenous lidocaine, tocainide, and mexiletine on spontaneously active fibers originating in rat sciatic neuromas, Pain, 38 (1989) 333. 7 Condouris, G.A., Local anesthetics as modulators of neural information. In: J.J. Bonica and D. Albe-Fessard (Eds.), Advances in Pain Research and Therapy, Vol. 1, Raven Press, New York, 1976. of local anesthetic agents. In: 8 Covino, B.C., Clinical pharmacology M.J. Cousins and P.O. Bridenbaugh (Eds.), Neural Blockade in Clinical Anesthesia and Management of Pain, 2nd Edn., Lippincott, Philadelphia, PA, 1988, Ch. 4. R., Parker, M. and Atkinson, A.J., Excessive serum 9 Davison, lidocaine levels during maintenance infusions: m~han~sms and prevention, Am. Heart J., 104 (1982) 203. 10 Dejard. A.. Petersen, P. and Kastrup, J., Mexiletine for the treatment of chronic painful diabetic neuropathy, Lancet, i (1988) 9. D.E., Loremo. B.. Werns, S. and Reidenberg, M.M., 11 Drayer.
Plasma levels. protem bindmg, and elimination data of lidocarnt~ and acttve metaboltter tn cardiac pattents of vartous ages. Clru Pharmacol. Ther.. 34 (1983) 14. 12 Dunlop, R.. Davies. R.J., Hockley. J. and Turner, P.. Analgesrc effects of oraf flecanide (Letter), Lancet. i (198X) 42.0. 13 Edwards, W.T.. Hahtb. F.. Burney. R.G. and Begm.
