Non-Opioid Pharmacology in Pediatric Pain Management

Lidocaine Infusions in Pediatric Pain

By James J. Mooney, MD
Medical Director, Pain Service
Children's Healthcare of Atlanta
Emory Healthcare
Department of Anesthesiology
Emory University School of Medicine
Atlanta, Georgia

Lidocaine, first developed in 1943 by Nils Löfgren and released in 19481,2, has found a variety of clinical uses outside of local infiltration and regional anesthesia. It was first used as an anti-arrhythmic in 19503, but more recent work has looked at its use in the settings of tinnitus, sepsis/infection and cancer.4–7 Pain remains its dominant use, and this article will look at the use of infusions and the implications for pediatric pain management.

Mechanism
The first amide local anesthetic, it was compared to, and quickly replaced, procaine1. Like the other local anesthetics in use, lidocaine is considered a sodium channel blocker. Interestingly, evidence would indicate the Nav 1.8 channel and Tetrodotoxin (TTX) sensitive neurons are significantly more sensitive to lidocaine than other channels or TTX resistant neurons.8,9 This theoretically holds the potential for selective use of lidocaine as Nav 1.8 may be more involved with visceral pain and accumulates in neuromas.10,11

In addition to the sodium channel activity, lidocaine has several other modes of activity (many of which have yet to be fully elucidated) that may play a role in pain management. At clinically relevant plasma concentrations, it has effects at the muscarinic M1 and M3, NMDA receptor (though effective concentration varies widely by study), purinoreceptor P2X (with a possibly antihyperalgesic effect), TLR4 (Toll like receptor 4, involved in pain models, but little evidence for a clear effect), nicotinic acetylcholine receptor, and GABA (the effects are mixed with unclear implications).9 At higher concentrations it has a number of other sites of activity, including potassium channels.9

Lidocaine seems to sensitize CB1 receptors  and attenuates interleukins (IL1, 6 and 8), intracellular adhesion molecule-1 (required for immune cell transport), TNF alpha activation of eNOS, and priming of neutrophils.8,9 It also seems to attenuate oxygen free radicals/lipid peroxidation. Other research has shown one of its two clinically active metabolites, monoethylglycinexylidide (MEGX, the other being glycinexylidide or GX), inhibits GlyT1. This should be an anti-nociceptive effect, and seems to ameliorate allodynia/hyperalgesia and reduce increased WDR neuron firing from inflammatory pain.9,12

In vivo research has provided some insight into the mechanisms of lidocaine’s activity as well.  When applied prophylactically, it seems to have significant impact on development of hyperalgesia and depending on the timing of application, flare formation.13,14 In one study comparing lidocaine to ketamine, which reduced ongoing and evoked pain to brush/pinprick, lidocaine only reduced evoked pain to repetitive pinprick stimuli.15

Kinetics
Lidocaine in plasma is 60-80% bound to proteins, predominantly alpha-1-glycoprotein, and crosses the blood brain barrier passively.9 When administered IV, the first peak half-life is 8-17 minutes, with a second slower phase half-life of 87-108 minutes. After a steady state has been achieved via infusion, the half-life is approximately two hours.16 Lidocaine is almost entirely eliminated by metabolism in the liver, predominantly by CYP450 1A2 and 3A4.17,18 Liver failure will slow the breakdown of lidocaine, but this seems to become significant only in severe failure (Childs class C). It can also be inhibited by medications, notably fluvoxamine, and erythromycin.17,18 Renal failure, in patients not receiving dialysis, leads to significantly increased clearance time and half-life. Volume of distribution and MEGX levels are independent of renal function, however. MEGX is only minimally excreted by the kidneys, but rather is converted to GX which is subsequently excreted. Lidocaine clearance seems to be inhibited by MEGX in one study, but this may also be a result of GX competitively inhibiting lidocaine’s metabolism (made particularly worse in the setting of renal failure).19,20

Safety/Toxicity
Initially felt to be safer than procaine, experience and research have highlighted some of the undesirable effects of lidocaine (and other local anesthetics)1. Fortunately, immediate type hypersensitivity reactions are rare.21 Overdose is a significant concern, though early literature discussed doses of 1.35 and 3 grams being administered leading to a declaration of 1 gram as a maximum dose1. More recently, local infiltration maximum doses are considered in the realm of 4.5mg/kg. However, myotoxicity (direct myopathy and myonecrosis) and neurotoxicity are known risks even at these doses22, and articular cartilage is known to suffer mitochondrial damage leading to cell death when directly exposed to lidocaine.23 In clinical practice, though, lidocaine infusions are generally kept within the realm of 0.5-5mcg/ml plasma levels when monitored.9

Adult Literature
As with many treatments, much of the literature is directed to the adult population. In a review by Masic et al., it has been shown to provide benefit in renal colic, critical limb ischemia, acute migraine, and radicular low back pain.24 It was also noted to be beneficial in the management of burn pain and sickle cell crisis.25,26 Intra-operative use was noted to reduce the need for anesthetic agents and opioids.27 Perioperatively, lidocaine has been shown to improve common benchmarks such as pain, opioid consumption, side effects, bowel function and time to discharge in procedures such as laparoscopic cholecystectomies, colorectal surgery, breast surgery and renal procedures.27–31 There is also evidence its use can reduce chronic post-surgical pain32,33 and has a protective effect on cell mediated immunity in radical hysterectomy34. There are numerous other studies addressing other surgical procedures.

In the chronic pain setting, it has been shown to be beneficial in a variety of headache conditions, post-stroke pain, Dercum’s disease, cancer pain, fibromyalgia, CRPS, erythromelalgia, and neuropathic pains including post-amputation pain.16,35–44 There is some work attempting to clarify which patients may receive benefit from lidocaine based on the pain descriptors, but this is an isolated work to date.45 However, it was shown the response to mexiletine can help predict who may benefit from the use of mexiletine subsequently.41,46

Pediatric Application
The availability of literature in the pediatric population is quite limited, predominantly consisting of case reports/series. Intraoperatively, it was looked at in elective tonsillectomies and was found to reduce post-op nausea and vomiting (PONV), but opioid use and pain scores were unchanged.47 In pediatric cancer, two retrospective studies have been released, looking at a total of 16 patients. Only the larger series by Lin examined opioid consumption, (where it was decreased) but both series demonstrated pain was dramatically reduced. Neither series reported significant side effects occurring.48,49 There are three case reports involving pediatric patients with erythromelalgia. They used both continuous (>24hrs) infusions and recurring short term infusions, but they all reported significant pain relief. 50–52 A review of outpatients receiving lidocaine infusions in the ambulatory setting reported 78% of infusions produced a reduction in pain scores during the infusion, with some evidence for more prolonged relief afterwards. This review had a variety of pain, including headache, neuropathic and musculoskeletal diagnoses.53

While there are no studies examining lidocaine’s toxicity in pediatrics, some studies have discussed side effects. In the cancer patient series, the only side effects noted were visual changes, visual hallucinations, and parasthesias.48,49 It should be noted that, although the study by Gibbons et al. looked at plasma levels they believe several of their samples were contaminated, limiting the ability to draw any safety conclusion. The review of ambulatory center infusions noted the most common side effects were numbness/tingling, dizziness, and nausea/vomiting, with no serious side effects.53 Only one of the patients with erythromelalgia had any note made of possible side effects, with a report of no adverse events noted.50

Unfortunately, guidance on dosing for the pediatric population is difficult based on the literature. Generally, extended infusions (longer than six hours) should be guided by frequent plasma levels until steady state is achieved in a range of 2-5mcg/ml. These longer infusions tend to have lower dosing, such as 15 or 16.5mcg/kg/minute. Maximum dose for these infusions were in the 50-60mcg/kg/minute range.49,50,52 The shorter infusions frequently either have significantly higher rates of infusions or loading doses. The erythromelalgia patient receiving intermittent infusions received 4mg/kg over three hours (which translates to 22.2mcg/kg/minute) while those in the ambulatory infusion center study received 40-60 mcg/kg/minute for two to six hours (accompanied by a magnesium dose in most cases, which theoretically may help to reduce side effects and complications)52,53. In the tonsillectomy study, patients received 1.5mg/kg over five minutes followed by 2mg/kg/hr until the end of the surgery.47

Summary
The literature for efficacy of lidocaine is still of generally low quality, though that can be said of most pain treatments. This is especially true in pediatrics. Given the multiple potential mechanisms of action attributed to lidocaine, it is entirely reasonable to consider lidocaine to have therapeutic potential in many patients when first or second lines of treatment are inadequate. The cumulative data for a relative lack of side effects should provide encouragement for pursuing this modality as well. Perhaps this review will promote the use of lidocaine infusions among practitioners and stimulate interest in research on its efficacy and safety.

References

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