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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. (1-7) 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. These studies and a review of the evidence available in 2004 indicated a need for additional randomized, controlled, and double-blinded studies to determine the incremental effects of lidocaine over active placebo, and compared to other standard treatments for chronic pain, such as the use of antidepressants for fibromyalgia. It was concluded that 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. In addition, further studies were needed to determine appropriate patient selection criteria, predictive values, effective dosage ranges, frequencies, and duration of treatment. Updates of the literature using the MEDLINE database were performed in 2006, 2007, 2008, and June 2009. Relevant evidence is described below.

Literature Review

Lidocaine

In a randomized, double-blind, placebo-controlled, crossover designed trial, Kvarnstrom and colleagues evaluated the effects of lidocaine in 12 patients with long-term peripheral neuropathic pain of traumatic origin. (1) The authors reported no significant differences in pain reduction over placebo on visual analogue scale (VAS). Wu et al evaluated the effects of IV lidocaine on 31 patients with post-amputation pain in a randomized, double-blind, active placebo-controlled, crossover trial. (2) 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. (3) However, the duration of this significance lasted only 45 minutes. Wallace et al reported on a randomized, double-blind, placebo-controlled study of 16 patients with complex regional pain syndrome types I and II. (4) While IV lidocaine significantly reduced the pain response to cool stimuli, mechanical pain relief was not significant. In a study of 24 patients with postherpetic neuralgia, Baranowski et al reported IV lidocaine provided significant pain reduction over placebo; (5) however, the pain was not eliminated. Medrik-Goldberg and colleagues evaluated 30 patients with sciatica in a randomized, double-blind, 3-arm crossover trial. (6) 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 1 hour after the 2-hour lidocaine infusion. However, the evaluation did not extend beyond the 3-hour treatment period. Finally, in a randomized, double-blind, crossover study of 18 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. (7) However, none of these patients responded to IV lidocaine alone.

The 2006 literature review update identified a randomized, double-blind crossover trial of IV lidocaine in 24 patients with spinal cord injury neuropathic pain. (8) 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. Tremont-Lukats and colleagues reported results of a randomized, double-blinded, placebo-controlled pilot trial in 32 subjects with ongoing neuropathic pain (9). 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. 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 (score of 0-10). (10) Forty-two of the patients (42%) met the criteria of 30% or greater pain reduction; some of this subset was subsequently treated with mexiletine.

A Cochrane review (11) 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. 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. A separate publication by the same authors estimated an 11-point (of 100) improvement in pain scales with IV lidocaine or oral analogues compared with placebo. (12) 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.” (13) In addition, the authors 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. Given the high frequency of side effects and the short duration of action, the health benefits of IV lidocaine remain unclear.

Ketamine

A comprehensive systematic review of the treatment of chronic neuropathic pain with IV ketamine, 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. (14) Some small randomized controlled trials were available for review, and 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 this treatment for 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.

One small randomized trial published after the 2003 systematic review was identified. Kvarnstrom and colleagues assessed the effect of sub-anesthetic levels of IV ketamine or lidocaine on pain after spinal cord injury. (15) 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.” Another study compared the efficacy of placebo, ketamine, calcitonin, and combined calcitonin and ketamine to relieve phantom limb pain (n =20, within subject design). (16) 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. A 2006 retrospective analysis described outpatient ketamine treatment in 13 patients with severe neuropathic pain; diagnoses included complex regional pain syndrome (n =8), migraine (n =1), neuropathy (n =3), and phantom limb (n =1). (17) 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% (VAS of 7.7 to 4.8) 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.

Multi-day courses of ketamine infusion in an inpatient setting have been reported for treatment of complex regional pain syndrome. A 2004 retrospective analysis described the effect of ketamine infusion in 33 patients with complex regional pain syndrome. (18) Inpatient infusion of a sub-anesthetic dose of ketamine over 2 to 20 days was found to provide relief for 9 months (median of 4 months). Twelve of the patients received a second infusion, with a reported mean relief duration of 25 months (median of 36 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.

In 2008, Kiefer et al. reported a multi-center (U.S. and Europe) prospective open-label phase II study of anesthetic dosing of ketamine in 20 patients with refractory complex regional pain syndrome. (19) Symptoms were either long-standing (range of 6 -68 months), spreading, or rapidly progressive, and refractory to conventional nonmedical (physical therapy, psychological approaches), or pharmacological (mono- or combined therapy) and interventional treatments (at least 3) including selective nerve blocks, epidural analgesia, brachial plexus blocks, sympathetic ganglion blocks, intravenous regional sympathetic blocks, spinal cord stimulation, surgical sympathectomy, or intrathecal drug delivery systems. Following consent, patients were intubated and mechanically ventilated (except for the first 3 patients). Ketamine infusion was titrated up to a dose of 7 mg/kg/h with infusion over 5 days, then tapered downwards until consciousness was attained. Midazolam was co-administered to a level of deep sedation to attenuate agitation and other side effects. All patients received IV low-dose heparin, the proton pump inhibitor pantopraxole, and clonidine to control cardiovascular and psychomimetic side effects of ketamine. Intubated patients received enteral nutrition with insulin as needed to maintain normoglycemia. Standard intensive care monitoring along with blood gas analysis, blood chemistry, and screening for infectious complications was performed regularly. Outcomes were assessed at 1 week and 1, 3, and 6 months after treatment. Pain intensity decreased from a numerical rating scale of 9 at baseline to 0.5 at 1 week and remained low (2.0) at 6 months. Three patients relapsed, but with lower pain (3.8) than at baseline. Pain relief was 94%, 89%, and 79% at 1, 3, and 6 months, respectively. Upper and lower extremity movement improved from 3.2 at baseline to 0.4 at 6 months for arm movement, and from 2.3 at baseline to 0.6 at 6 months for walking. At six months, there was a significant difference in the ability to perform activities of daily living; one patient rated total impairment, 3 severe impairment, 6 moderate impairment, and 10 patients no impairment. Impairment in the ability to work was rated at baseline as complete by 11, severe by 5, and as moderate by four patients. At 6 months, 2 patients remained unable to work, 4 had moderate impairment, and 14 patients reported no impairment. Psychotropic side effects resolved in the first week in the majority of patients, although 5 patients reported difficulties with sleeping and recurring nightmares for a month following treatment. Muscle weakness was reported in all patients for as long as 4-6 weeks following treatment. As indicated by the authors, a strong placebo response to this intensive intervention might be expected, and a large, multicenter randomized controlled trial would be needed to definitively establish efficacy and safety. At this time, the beneficial effect of intravenous administration of ketamine is considered suggestive but not proven; additional trials are needed.

Summary

Intractable pain presents a great challenge to patients and their healthcare providers. Recent evidence suggests that IV courses of lidocaine and ketamine may provide at least temporary relief to some chronic pain patients. However, the severity of side effects raises questions about the overall health benefit of this procedure. Additional clinical trials under carefully monitored and controlled conditions are needed to evaluate treatment protocols, including the co-administration of treatments to attenuate the serious side effects of these agents. Double-blind, placebo-controlled studies are also needed to establish the long-term safety and efficacy of sodium channel and N-methyl-D-aspartate (NMDA)-antagonists in the treatment of chronic neuropathic pain. Therefore, this treatment is considered investigational.

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Index

Policy History