Coverage Policy Manual
Policy #: 2004018
Category: Medicine
Initiated: May 2004
Last Review: May 2018
  Intravenous Lidocaine or Ketamine for the Outpatient Management of Chronic Pain

Description:
Intravenous (IV) infusion of anesthetics such as ketamine or lidocaine has been reported for the treatment of chronic pain from fibromyalgia and neuropathic pain disorders including phantom limb pain, post-herpetic neuralgia, complex regional pain syndromes, diabetic neuropathy, and pain related to stroke or spinal cord injuries. Chronic pain may consist of thermal or mechanical allodynia, dysesthesia, and/or hyperalgesia that continue for a period of time, such as over 6 months, or longer than clinically expected after an illness or injury. Allodynia is when pain occurs from a stimulus that normally does not elicit a painful response (e.g., light touch, warmth). Dysesthesia is when there is a constant or ongoing unpleasant or electrical sensation of pain. Hyperalgesia is when there is an exaggerated response to normally painful stimuli.
 
IV infusion of anesthetic agents may be given in the inpatient or outpatient setting as part of a pain management program.* The infusion of a sub-anesthetic dose may be preceded by a bolus infusion to achieve desired blood levels sooner. Lidocaine, which prevents neural depolarization through effects on voltage-dependent sodium channels, is also used systemically for the treatment of arrhythmias. Adverse effects for lidocaine are common and can be mild to moderate, including general fatigue, somnolence, dizziness, headache, periorbital and extremity numbness and tingling, nausea, vomiting, tremors, and changes in blood pressure and pulse. Severe adverse effects can be arrhythmias, seizures, loss of consciousness, confusion, or even death. Lidocaine should only be given IV to patients with normal conduction on electrocardiography and normal serum electrolyte concentrations to minimize the risk of cardiac arrhythmias.
 
Ketamine is an antagonist of the N-methyl-d-aspartate (NMDA) receptor and a dissociative anesthetic. It is the sole anesthetic agent approved for diagnostic and surgical procedures that do not require skeletal muscle relaxation. Respiratory depression may occur with overdosage or too rapid a rate of administration of ketamine; it should be used by or under the direction of physicians experienced in administering general anesthetics. Ketamine is a schedule III controlled substance. Psychological manifestations vary in severity from pleasant dream-like states to hallucinations and delirium, and can be accompanied by confusion, excitement, aggression, or irrational behavior. The occurrence of side effects with IV anesthetics may be reduced by the careful titration of sub-anesthetic doses. However, the potential benefits of pain control must be carefully weighed against the potential for serious, harmful side effects.
 
Test infusion of ketamine or lidocaine has also been used in treatment planning to assess patient responsiveness to lidocaine to determine whether medications such as oral mexiletine or oral ketamine may be effective.
 
This policy does not address lidocaine or ketamine administered by continuous subcutaneous infusion for chronic pain. Nor does it address the use of IV lidocaine or ketamine in the inpatient setting.
 
IV lidocaine is FDA approved systemically for the treatment of arrhythmias and locally as an anesthetic. IV lidocaine for the treatment of chronic pain is an off-label usage.  Ketamine hydrochloride injection is FDA approved for diagnostic and surgical procedures that do not require skeletal muscle relaxation, for the induction of anesthesia prior to the administration of other general anesthetic agents, and to supplement low-potency agents, such as nitrous oxide.  IV ketamine for the treatment of chronic pain is an off-label use.

Policy/
Coverage:
EFFECTIVE MAY 2018
 
Intravenous lidocaine or ketamine for the outpatient management of chronic pain does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, intravenous lidocaine or ketamine for the outpatient management of chronic pain is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.
 
Ketamine injections for treatment of mental health disorders does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, ketamine injections for treatment of mental health disorders is considered investigational. Investigational services are an exclusion in the member certificate of coverage.
 
EFFECTIVE PRIOR TO MAY 2018
 
Intravenous lidocaine or ketamine for the outpatient management of chronic pain does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, intravenous lidocaine for the outpatient management of chronic pain is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Rationale:
A review of the peer-reviewed literature on MEDLINE for the period of 1994 through February 2004 revealed that the degree and duration of pain relief with IV lidocaine does not appear to be clinically significant in the majority of patients.   While some patients have reported diminished pain concurrent with the IV administration of lidocaine that may continue beyond the infusion period for an extended duration, overall, responses to IV lidocaine in relief of allodynia, dysesthesia and hyperalgesia have been mixed.
 
The available evidence in peer-reviewed publications on the use of IV lidocaine for chronic pain is lacking.  Information on patient selection criteria, treatment protocols, long tern benefits and comparisons to standard pain management therapy or alternatives is not available.  In general, reported regimens for IV lidocaine have been single-episode lidocaine infusions of one to two hours duration.  Outcomes assessed have included reductions in pain using VAS scales and verbal reports; durations of pain relief; and the absence of adverse side effects. In the literature available, duration of pain relief has only been measured over a short period of time (from one hour to five days).  Therefore, IV lidocaine does not appear to be intended to provide long term pain relief, but only short term relief.  What role short term relief for chronic pain serves in the overall management of the patient is not clear. There are no studies to compare IV lidocaine to standard treatment for pain management (i.e., oral medications, physical therapy, behavioral and cognitive therapy, etc,) or other alternatives (e.g., spinal cord stimulation, electrical stimulation devices, etc.). Additionally, the available literature focuses on IV lidocaine therapy for patients with a variety of chronic pain etiologies but there are no studies defining appropriate patient selection criteria.
 
In a randomized, double-blind, placebo-controlled, cross-over designed trial, Kvamstrom and colleagues evaluated the effects of lidocaine in twelve patients with long-term peripheral neuropathic pain of traumatic origin.  The authors reported no significant differences in pain reduction over placebo on a visual analogue scale (VAS).   Wu, et al, evaluated the effects of IV lidocaine on 31 patients with postamputation pain in a randomized, double-blind, active placebo-controlled, crossover trial.  Wu and colleagues found stump pain was significantly reduced with IV lidocaine, yet phantom pain was not relieved and the stump pain relief was short-lived.  In a double-blind, placebo-controlled, crossover study of 16 patients either poststroke or spinal cord injury, Attal and colleagues reported IV lidocaine significantly reduced pain over placebo.  However, the duration of this significance lasted only 45 minutes.   Wallace, et al, reported on a randomized, double-blind, placebo-controlled study of sixteen patients with complex regional pain syndrome types I and II.   While IV lidocaine significantly reduced the pain response to cool stimuli, mechanical pain relief was not significant.  In a study of 24 patients with postherpefc neuralgia, Baranowski et al, reported IV lidocaine provided significant pain reduction over placebo.  However, the pain was not eliminated.  Medrik-Goldberg and colleagues evaluated 30 patients with sciatica in a randomized, double-blind, three-arm crossover trial.  The authors found lidocaine significantly reduced spontaneous pain as reported by VAS and pain evoked by straight leg raises. The pain reduction continued during saline infusion for one-hour post the two-hour lidocaine infusion. However, the evaluation did not extend beyond the 3 hour treatment period.  Finally, in a randomized, double-blind, crossover study of eighteen patients with fibromyalgia, Sorensen and colleagues found mixed responses with IV lidocaine with ketamine, morphine or both suggesting that pain processing mechanisms must differ in fibromyalgia.  However, no patients responded to IV lidocaine alone.
  
The above studies and a review of the evidence demonstrate a need for a further studies that are randomized, controlled and double-blinded, to determine the incremental effects of lidocaine over active placebo and as compared to other standard treatments for chronic pain, such as the use of antidepressants for fibromyalgia.   A placebo response due to the significant side effects with IV lidocaine warrants the use of active placebos to increase the probability of determining the true analgesic effect of Lidocaine in clinical trials. Additionally, further studies are needed to determine appropriate patient selection criteria, predictive values, effective dosage ranges, frequencies and duration of treatment.
 
Additional Information
The American Academy of Neurology guideline for the treatment of migraine headache indicates: "Evidence is insufficient at this time to establish a defined role for intranasal lidocaine or lidocaine intravenous in the management of acute migraine headache."   In 1994, the ANCPR noted in its guideline on the Management of Cancer Pain that "Systemically administered local anesthetic (intravenous lidocaine, oral mexiletine, and tocainide) and antiarrhythmic agents have been used clinically to treat neuropathic pain, although this is not currently an FDA-approved indication for these drugs."   No other professional society guidelines mentioning the use of IV lidocaine for chronic pain could be found.
 
2006 Update
A literature review update identified 1 randomized, double-blind crossover trial of IV lidocaine in 24 patients with spinal cord injury neuropathic pai. (Finnerup et al, 2005). In this trial, spontaneous and evoked pain were significantly reduced on VAS as measured before infusion and 25–35 minutes after the start of the infusion. Mostly mild adverse effects (experienced by 19 patients) and the relief of pain formed the basis of 21 patients identifying the lidocaine treatment period correctly. Identification of the correct treatment group draws into question whether successful blinding was achieved in this study, thus limiting interpretation of results. This also suggests the need for an active placebo in future trials, as noted. The authors concluded that intravenous lidocaine (and like agents) may be a treatment option for spinal cord injury pain. Although, the authors note, long-term treatment with lidocaine is usually not suitable.
 
A Cochrane review examined controlled clinical trials on lidocaine and its oral analogs (i.e., mexiletine, tocainide, and flecainide) for neuropathic pain treatment and found these drugs safely provided more pain relief than placebo and with similar effectiveness as other analgesics (Challapalli et al, 2005). The Cochrane review noted further investigation is needed to determine the clinical meaning of statistically significant pain relief and to test for less toxic analogs.
 
2007 Update
A search of the MEDLINE database was performed for the period of March 2006 through May 2007 on the IV administration of lidocaine for chronic pain. A meta-analysis by the authors of the Cochrane review described above estimated an 11-point improvement in pain scales with IV lidocaine or oral analogues compared with placebo (Tremonts-Lukats et al, 2005). Although side effects were reportedly not significantly different from other active controls (amitriptyline, carbamazine, gabapentin, morphine), the severity and nature of the adverse events could not be assessed. As indicated in an accompanying editorial, “the limitations of the contributing studies preclude drawing useful conclusions about the adverse effect profiles of these drugs” (Rathmell et al, 2005).  In addition, Tremont-Lukats and colleagues noted that 1) lidocaine’s short serum half-life (120 min) precludes the use of this drug for chronic use, and 2) all of the trials measured pain relief within 24 hours because in most patients the effect disappears a few hours after treatment. In 2006, Tremont-Lukats and colleagues reported results of a randomized, double-blinded, placebo-controlled pilot trial in 32 subjects with ongoing neuropathic pain (Tremonts-Lukats et al, 2006). Infusion of 5 mg/kg/h, but not 1 or 3 mg/kg/h, over a period of 6 hours was observed to decrease pain by about 30%. This effect lasted for the next 4 hours of observation. Side effects were frequent; in 2 subjects, infusion was terminated early due to bothersome side effects. Given the high frequency of side effects and the short duration of action, the health benefits of IV lidocaine have remained unclear.
 
A search of the MEDLINE database was also performed through May 2007 on the treatment of chronic pain with IV ketamine. A comprehensive systematic review of this topic, published in 2003, assessed the quality of evidence for ketamine’s effectiveness in central pain, complex regional pain syndromes, fibromyalgia, ischemic pain, nonspecific pain of neuropathic origin, acute pain in patients with chronic neuropathic pain, orofacial pain, phantom/stump pain, and postherpetic neuralgia (Hocking et al, 2003).  Some small randomized controlled trials were available for review; meta-analysis was considered not appropriate. The report concluded that despite the use of ketamine for over 30 years, there was insufficient evidence to advocate the routine use of ketamine in patients with chronic pain. Of particular concern were the significant side effects of this NMDA receptor antagonist in the central and peripheral nervous system. Few data were available concerning appropriate dosing and long-term administration. A 2003 Cochrane review also concluded that although 2 small trials suggested that ketamine given with morphine may help to control cancer pain, the data were insufficient to assess the effectiveness of ketamine in this setting (Bell et al, 2003).
 
The search identified 1 small randomized trial published after 2003. Kvarnstrom and colleagues assessed the effect of sub-anesthetic levels of IV ketamine or lidocaine on pain after spinal cord injury (Kvarnstrom et al, 2004). This randomized, double-blind, placebo-controlled crossover design found a 38% reduction in pain during ketamine infusion, with 5 of 10 subjects responding to treatment, compared with 1 of 10 in the lidocaine and 0 of 10 in the placebo groups. No significant pain reduction was observed following IV administration of lidocaine or saline. Adverse events were common with both treatments; ketamine produced 39 side-effects in 9 of 10 subjects. These included somnolence, dizziness, out of body sensation, changes in hearing and vision, paraesthesia, and other “unpleasant experiences.”
 
A recently published retrospective analysis described outpatient ketamine treatment in 13 patients with severe neuropathic pain; diagnoses included complex regional pain syndrome, migraine, neuropathy, and phantom limb (Webster et al, 2006). Low-dose ketamine (beginning at 0.12 mg/kg/h with slow upward titration) was delivered by a programmable pump through a peripherally inserted central catheter (PICC) line. With an average infusion duration of 16 days, pain severity decreased 38% with an 85% response rate. About half of the patients reported a perceived benefit 1 month after treatment. Side effects included fatigue, dizziness, confusion, and spinal pain. No patients reported hallucinations.
 
Inpatient infusion of ketamine has been reported for complex regional pain syndrome and intractable cancer pain. A 2004 retrospective analysis described the effect of ketamine infusion in 33 patients with complex regional pain syndrome (Correll et al, 2004). Infusion over 2 to 20 days was found to provide relief for 9 months. Twelve of the patients received a second infusion, with a reported mean relief duration of 25 months. Dosing was titrated by the occurrence of side effects, which included a feeling of inebriation, dizziness, blurred vision, or nausea. Hallucinations occurred in 6 of the 33 patients. Another retrospective study described efficacy of IV ketamine in 12 patients with intractable cancer pain (Lossignol et al, 2005). The authors reported that with continuous IV infusion of ketamine they were able to reduce the total daily dose of morphine by 50%, and 8 patients were able to go home with a portable pump. Pain, which was rated at 7–9 on a VAS scale before treatment with ketamine, was reported to remain acceptable until death without “intolerable” side effects.
 
Intractable pain presents a great challenge to patients and their healthcare providers. Although there is some evidence that infusion of sub-anesthetic doses of ketamine or lidocaine can provide temporary relief to some chronic pain patients, the severity of side effects raises questions about the overall health benefit of these treatments. The benefit of IV administration is unclear. Double-blind, placebo-controlled studies are needed to demonstrate long-term safety and efficacy. Studies are also needed to determine optimal dosing and duration of treatment for specific pain disorders.
 
2008 Update
A search of the MEDLINE database was conducted for the period of June 2007 through May 2008. The evidence identified does not alter the conclusions reached previously. In a retrospective analysis, 104 patients with suspected neuropathic pain who had undergone diagnostic IV lidocaine were found from screening 635 sequential charts; of these, 5 patients had requested discontinuation mid-infusion, resulting in a cohort of 99 patients with baseline and post-treatment numerical pain ratings (Carroll et al, 2007). Forty-two of the patients met the criteria of 30% or greater pain reduction; some of this subset was subsequently treated with mexiletine. Another study compared the efficacy of placebo, ketamine, calcitonin, and combined calcitonin and ketamine to relieve phantom limb pain (Eichenberger et al, 2008). One-hour infusion of ketamine or ketamine plus calcitonin resulted in >40% improvement in pain immediately after treatment. The mean and maximum pain scores remained significantly better than placebo for 48 hours after treatment. As concluded here, additional study is needed to determine the safety and efficacy of N-methyl-D-aspartate (NMDA)-antagonists for the treatment of chronic neuropathic pain. Intravenous administration of anesthetics has not been shown to improve the net health outcome. Therefore, there in no change in the policy statement.
 
2009 Update
A search of the MEDLINE database was conducted for the period of June 2008 through April 2009.  There were no randomized controlled trials noted that would prompt a change in the coverage.  Therefore, the policy remains unchanged.
 
2010 Update
A review of the literature has been conducted through August 2010.  There was no new literature identified that would prompt a change in the coverage statement.
 
2012 Update
A literature search conducted through September 2012 did not reveal any new information that would prompt a change in the coverage statement. Two new publications involving the use of ketamine for the treatment of pain were identified.
 
In 2011, Noppers et al. reported a randomized, double-blind, active placebo-controlled trial that was conducted in Europe using a 30-minute infusion of S(+)-ketamine (n=12) or midazolam (n=12) in patients diagnosed with fibromyalgia (Noppers, 2011). Baseline VAS pain scores were 5.4 in the ketamine group and 5.8 in the midazolam group. At 15 minutes after termination of infusion, significantly more patients in the ketamine group showed a reduction in VAS pain of greater than 50% compared to placebo. There was no significant difference between the groups at 180 minutes after infusion, at the end of week 1 or end of week 8. There was no difference between groups on the fibromyalgia impact questionnaire measured weekly over 8 weeks. In this well-conducted study, a short infusion of ketamine (30 minutes) did not have a long-term analgesic effect on fibromyalgia pain.
 
A 2012 retrospective analysis from an academic medical center in the U.S. identified 49 patients with severe refractory pain who had undergone 369 outpatient ketamine infusions during a 5-year period (Patil, 2012). Eighteen patients were diagnosed with CRPS, and 31 had other diagnoses including refractory headache (n=8) and severe back pain (n=7). All patients exhibited signs of central sensitization. Following pretreatment with midazolam and ondansetron, ketamine infusions were administered at the highest tolerated dose for a duration ranging from 30 minutes to 8 hours. The interval between infusions ranged from 12-680 days (median of 233.7 days). The immediate reduction in VAS was 7.2 for patients with CRPS and 5.1 for non-CRPS pain. Query of available patients (59%) indicated that for 38%, pain relief lasted more than 3 weeks. Adverse events, which included confusion and hallucination, were considered minimal.
 
2013 Update
A literature search was conducted using the MEDLINE database through September 2013.  No new information was identified that would prompt a change in the coverage statement.
 
2014 Update
 
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2015 Update
A literature search conducted using the Medline database through September 2015 did not reveal any new information that would prompt a change in the coverage statement.   
 
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.
 

CPT/HCPCS:
J2001Injection, lidocaine HCl for intravenous infusion, 10 mg

References: Attal N, Gaude V, et al.(2000) Intravenous lidocaine in central pain: a double-blind, placebo-controlled, psychophysical study. Neurology 2000; 54:564-74.

Baranowski AP, DeCourcey J, Bonello E.(1999) A trial of intraveous lidocaine on the pain and allodynia of postherpatic neuralgia. J Pain Symptom Manage 1999; 17:429-33.

Bell R, Eccleston C, Kalso E.(2003) Ketamine as an adjuvant to opiods for cancer pain. Cochrane Database Syst Rev 2003;(1):CD003351.

Carroll I, Gaeta R, Mackey S.(2007) Multivariate analysis of chronic pain patients undergoing lidocaine infusions: increasing pain severity and advancing age predict likelihood of clinically meaningful analgesia. Clin J Pain 20-07; 23(8):702-706.

Challapalli V, Tremont-Lukats IW, McNicol ED et al.(2005) Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev 2005; (4):CD003345.

Correll GE, Maleki J, Gracely EJ et al.(2004) Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med 2004; 5(3):263-275.

Eichenberger U, Neff F, Sveticic G et al.(2008) Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds. Anesth Analg 2008; 106(4): 1265-1273.

Finnerup NB, Biering-Sorenson F, Johannesen Il et al.(2005) Intravenous lidocaine relieves spinal cord injury pain: a randomized controlled trial. Anesthesiology 2005; 102(5): 1023-1030.

Hocking G, Cousins MJ.(2003) Ketamine in chronic pain management: an evidence-based review. Anesth Analg 2003; 97(6):1730-1739.

Kvarnstrom A, Karlsten R, et al.(2001) The effectiveness of intravenous ketamine and lidocaine on peripheral neuropathic pain. Acta Anaesthesiol Scand 2001; 47:868-77.

Kvarnstrom A, Karlsten R, Quiding H et al.(2004) The analgesic effect of intravenous ketamine infusions for neuropathic pain. Acta Anaesthesiol Scand 2004; 48(4):498-506.

Lossignol DA, Obiols-Portis M, Body JJ.(2005) Successful use of ketamine for intractable cancer pain. Support Care Cancer 2005; 13(3):188-193.

Medrik-Goldberg T, Lifschitz D, et al.(1999) Intravenous lidocaine, amantadine, and placebo in the treatment of sciatica: a double-blind, randomized, controlled study. Reg Anesth Pain Med 1999; 24:534-40.

Noppers I, Niesters M, Swartjes M et al.(2011) Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: a randomized, prospective, double blind, active placebo-controlled trial. Eur J Pain 2011; 15(9):942-9.

Patil S, Anitescu M.(2012) Efficacy of outpatient ketamine infusions in refractory chronic pain syndromes: a 5-year retrospective analysis. Pain Med 2012; 13(2):263-9.

Rathmell JP, Ballantyne JC.(2005) Local anesthetics for the treatment of neuropathic pain: on the limits of meta-analysis. Anesth Analg 2005; 101(6): 1736-1737.

Silberstein SD for US Headache Consortium.(2000) Practice Parameter: Evidence-based guidelines for migraine headache (An evidence-based review). Neurology 2000; 55:754-62.

Sorenson J, Bengtsson A, et al.(1997) Fibromyalgia - are there different mechanisms in the processing of pain? A double blind crossover comparison of analgesic drugs. J Rheumatol 1997; 24:1615-21.

Tremont-Lukats IW, Hutson PR, Backonja MM.(2006) A randomized, double-masked, placebo-controlled pilot trial of extended IV lidocaine infusion for relief of ongoing neuropathic pain. Clin J Pain 2006; 22(3):266-271.

Tremont-Lukats, IW, Challapalli V, McNicol ED et al.(2005) Systemic administration of local anesthetics to relieve neuropathic pain: a systmeatic review and meta-analysis. Anesth Analg 2005; 101(6):1738-1749.

Wallace MS, Ridgeway BM, et al.(2000) Concentration-effect relationship of intravenous lidocaine on the allodynia of complex regional pain syndrome types I and II. Anesthesiology 2000; 92:75-83.

Webster LR, Walker MJ.(2006) Safety and efficacy of prolonged outpatient ketamine infusions for neuropathic pain. Am J Ther 2006; 13(4):300-305.

Wu CL, Tella P, et al.(2002) Analgesic effects of intravenous lidocaine and morphine on postamputation pain: a randomized double-blind, active placebo-controlled, crossover trial. Anesthesiology 2002; 96:841-8.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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