Lidocaine Infusion: A Promising Therapeutic Approach for Chronic Pain

Opioid abuse is a national epidemic in the United States, where it is estimated that a prescription drug overdose death occurs every 19 minutes. While opioids are highly effective in acute and subacute pain control, their use for treatment of chronic pain is controversial. Chronic opioids use is associated with tolerance, dependency, hyperalgesia. Although there are new strategies and practice guidelines to reduce opioid dependence and opioid prescription drug overdose, there has been little focus on development of opioid-sparing therapeutic approaches. Lidocaine infusion has been shown to be successful in controlling pain where other agents have failed. The opioid sparing properties of lidocaine infusion added to its analgesic and antihyperalgesic properties make lidocaine infusion a viable option for pain control in opioid dependent patients. In this review, we provide an overview of the opioid abuse epidemic, and we outline current evidence supporting the potential use of lidocaine infusion as an adjuvant therapeutic approach for management of chronic pain.


Introduction
Chronic pain is a debilitating condition that frequently requires treatment with high doses of opioids [1]. Chronic pain affects as many as 116 million adult Americans each year with an annual estimated cost of 635 billion dollars or more in medical costs and lost wages [2]. A generalized definition of chronic pain is "Pain that extends beyond the expected period of healing" [3]. The temporal definition of chronic pain varies, but it is often described as pain This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. that persists for more than 3 months or more than 6 months. According to the NIH, pain is one of our most pressing national public healthcare problems and as a result chronic pain was named by the NIH as the "silent epidemic" [4]. The prevalence of chronic pain is hard to assess due to the complexity of chronic pain and variance in the definition [5].
Despite advances in the specialty of pain management, chronic pain continues to be on the rise. Results from the 2012 National Health Interview Survey showed that about 25.3 million U.S. adults (11.2%) had pain almost every day for the preceding 3 months, with a staggering 40 million adults (17.6%) complained of significant or severe pain [6]. In an effort to raise awareness of the prevalence of chronic pain, the American Pain Society endorsed pain as fifth vital sign in 1999. Since this endorsement, there has been an escalating rise in the number of opioid prescriptions for chronic non-cancer pain where opioids have become the standard of care for moderate to severe pain [6][7][8][9]. This shift in practice is clearly reflected in the dramatic increase in the medical use of the four most common used opioids for pain. Since 1997, for example, morphine use has increased by 73%, hydromorphone by 96%, fentanyl by 226% and oxycodone by 403% [10]. Despite their frequent use, opioids are only partially effective for short-term pain relief and have highly variable effectiveness in the long term relief (greater than 6 months) of pain [11].
Thus far, there has been little progress on for alternative non-invasive therapeutic strategies for chronic pain patients maintained on opioids. Rightfully so, much of the effort has been focused on improving patient compliance and prescription practices. Therefore, the approach to the current opioid abuse epidemic requires not only implementation of safer practice guidelines, but also novel therapeutic approaches. In the current review, we provide an overview of the magnitude of the current epidemic of prescription opioid abuse and outline the potential of lidocaine infusion as a viable therapeutic strategy for pain control in opioid dependent patients, where lidocaine infusion has the potential to markedly reduce the dependence on opioids both in the acute and chronic settings.

Opioid Use Disorder
In concordance with the increase of opioid prescriptions, the incidence of opioid use disorder has markedly increased. This is now one of the major health problems in the United States, with almost a daily increasing morbidity and mortality due to opioids misuse and abuse [12,13]. Recent studies clearly highlight the significant increase in opioid use, abuse, and overdose mortality due to prescription opioids [14]. There is currently an excess of 1300 deaths per year due to drug overdose involving prescription opioids. Importantly death resulting from drug overdose in general has now become the leading cause of death in the 35 to 54 age group, exceeding motor vehicle accidents [15]. This increase in opioid related complications has led the FDA to propose a risk evaluation and mitigation strategy (REMS), which applies to all long acting and immediate release opioids. In addition, this advisory panel also advocated that education for safe prescribing practices of opioids become mandatory for all prescribing physicians [16]. An important reason for the current opioid epidemic is the fact that a shift in practice in the form of leniency in opioid prescription has gradually occurred over the past two decades. This gradual shift in practice patterns has resulted in a dramatic increase in opioid sales, as well as prescription drug abuse overdoses.
Despite the pressing need for formulating a comprehensive response to this problem, responding to concerns regarding opioid prescription patterns places a significant burden on providers involved in treating pain as they strive to balance the need to address the needs of their patients, and at the same time avoiding, over-prescribing, while monitoring opioids misuse and abuse [17]. Another recent advance that occurred in 2015 is that all hydrocodone-containing products officially became schedule II drugs, which immediately made it exceedingly more difficult to overprescribe, and prevented mid-level providers for administering these medications without oversight from physicians. The impact this change will have on the current opioid misuse epidemic however, remains to be seen.

Complications associated with chronic opioid use
Chronic treatment with opioids results in a wide array of side effects including addiction, tolerance, immune modulation, as well as abnormal pain sensitivity [18]. Therefore, although opioids were initially thought to be the solution for chronic pain, opioid use has markedly exacerbated chronic pain and complicated its treatment [19]. As a result, it is now advocated that physicians adopt a far more cautious approach towards escalating opioid doses in patients suffering from chronic pain, given the large body of evidence supporting the notion that chronic opioid use of is neither safe nor effective [18].
In addition to the aforementioned complications, current evidence suggests that a more complex range of side effects that are associated with chronic opioid have been overlooked. For example, neuronal plasticity at the spinal dorsal horn level or more central in the rostroventral medulla and hippocampus results in a marked increase in pain sensitivity [20]. The effect of opioids on the neuroendocrine system has been extensively studied in animal models and in humans. Vuong et al reviewed this topic extensively, and found that although the chronic opioid changes were more relevant for opioid addiction, most of the studies highlighted acute changes in the neuroendocrine function as a result of opioid treatment. Nevertheless, the reviewed literature suggests that opioid use results in hypogonadism and weight gain by decreasing luteinizing hormone and increasing growth hormone [21]. Moreover, opioids have been known for sometime to exert an immune modulatory effect, for example morphine inhibits resistance to bacterial infection in guinea pigs [22,23]. This mechanism of this immunomodulatory effect is now quite understood, however some explanation may be provided through the expression of classic and novel opioid receptors by immune cells, which is believed to mediate the inhibitory action of opioids on proliferation of immune cells [23,24]. In addition, chronic opioid use has been shown to exert a potent immuneinhibitory effect, which is of particular concern in immune-compromised HIV infected, and the elderly patients [25]. For example, opioid use has been shown to increase the risk of pneumonia in older adults; where the odds of developing pneumonia were found to be 1.38 in elderly opioid users (95% confidence interval (CI) = 1.08-1.76) versus nonopioid users. Although the risk of these changes is highest in the first 14 days of use, there was a significant increase in risk of developing pneumonia with long-acting opioids (OR) (3.43 (95% CI = 1.44-8.21) versus non-opioid users, as well as with short-acting opioids, OR was 1.27 (95% CI = 0.98-1.64) versus non opioid users. Interestingly, in the same population the risk of pneumonia was not observed with other drugs like benzodiazepines [26].

Chronic opioid use increases pain
In order to develop novel therapeutics for management of chronic pain, a comprehensive understanding of underlying mechanisms is critical. An important mechanism of the pathophysiology of chronic pain is the development of a maladaptive inflammatory response, which mediates pain sensation well after the initial insult is gone. For example, macrophages and lymphocytes have been shown to invade dorsal root ganglia (DRG) after acute injury in rodent models [27]. Although this is essential for the initial wound healing response, they can mediate a maladaptive response if they persist following the acute injury phase. This is partly mediated by secretion of proinflammatory cytokines, which generate spontaneous firing in sensory neurons. These spontaneous firings of sensory nerves mediate the progression of acute pain into chronic neuropathic pain [27]. Proinflammatory cytokines also play an important role in peripheral and central sensitization which causes an increase in both the duration and severity of pain [28].
Chronic administration of opioids also results in a an increase in levels of circulating inflammatory cytokines such as interleukin 6 (IL6), interleukin 1B (IL1B), and tumor necrosis factor (TNF). The increase in these cytokines results in hyperalgesia and increased pain [29]. Although the concomitant use of anti-inflammatory drugs has been advocated to reverse this inflammatory response, their effect have proven to be suboptimal and is results in increased complications effects such renal gastrointestinal, and cardiovascular side effect, all which contribute to a significant increase in morbidity and mortality. Therefore, current evidence highlights the lack of mechanistic basis for escalating the use of opioids for chronic pain given the known effect of chronic opioid use in pain sensitization ( Figure 1).
A plausible strategy to interrupt the vicious cycle of pain, inflammation and hyperesthesia is using efficacious, non-opioid medications for the treatment of chronic pain. This evidence calls for a newer pharmacotherapeutic approach that effects peripheral and central sites of action and could ultimately reverse this neuroplasticity. Such a drug could potentially relieve pain in opioid dependent patients and potentially be used as an adjuvant treatment in opioid abuse treatment programs to prevent relapse.

Systemic Lidocaine for Treatment of Neuropathic Pain
Lidocaine infusion has been used to treat some acute and chronic pain conditions. It was first used for treatment of neuropathic pain due to burns in 1943 [30]. Since then lidocaine has only been tested in a few studies on a small number of chronic pain patients, such as patients with diabetic neuropathy and complex regional pain syndromes [31,32]. In neuropathic pain, the pathophysiology involves the modification of expression of sodium channels leading to the plasticity of responses responsible for the generation of inappropriate pain [33]. Lidocaine attenuates peripheral nociceptors sensitization and central hyperexcitability through its sodium channel blocking action [33].
Lidocaine also has other modes of actions that explain its clinical role in treating peripheral and central pain. It has potent anti-inflammatory properties that are more potent than traditional anti-inflammatory drugs, with fewer side effects [34,35]. Through its antiinflammatory property, lidocaine infusion has been shown to reduce circulating inflammatory cytokines [34]. The role of inflammatory cytokines is recognized in the process of secondary hyperalgesia and central sensitization [27]. Lidocaine infusion is specifically effective in relieving the mechanical allodynia and hyperalgesia associated with chronic neuropathic pain. This process is believed to occur through a central mechanism of action ( Figure 2) [36].
Wallace et al.
[37] evaluated the effects of I.V. lidocaine on sensory thresholds in complex regional pain syndrome (CRPS) patients. Patients received IV of lidocaine and diphenhydramine 1 week apart. The investigators measured pain scores and performed neurosensory testing. The results of this study indicated that intravenous lidocaine affects cold stimuli-related pain more significantly than mechanical pain. This demonstrates that lidocaine may primarily exert its effect on sensory processing as opposed to conduction blockade. Attal et al. [38] showed that intravenous lidocaine significantly reduced spontaneous pain and mechanical hyperalgesia. The same group also showed in a separate study [39] that lidocaine reduced neuropathic pain but did not change dynamic mechanical pain thresholds in non-neuropathic areas. Taken together, these results suggest lidocaine exerts a central modality-specific effect rather than a general pain-relieving effect. Importantly, these findings suggest that is critical to avoid reliance on visual analogue scale as a single method of assessing response to lidocaine.
In a meta-analysis, Tremont-Lukats et al. [40] noted that there is a wide variation of doses and durations of lidocaine administration for treatment of neuropathic pain, nevertheless the authors concluded that while low doses of lidocaine did not confer benefit over placebo, higher doses showed modest effect on the VAS. This meta-analysis highlights the need for standardized lidocaine administration protocols.
An important randomized, double blind, placebo-controlled clinical trial was controlled clinical trial was conducted in patients with neuropathic pain by Gottrup et al. [41]. In this study, patients were randomized to 0.24 mg/kg ketamine, to 5 mg/kg lidocaine or saline infusion, and the effect on on going or evoked pain (brush or pin-prick) was assessed. The results demonstrate that ketamine reduced both on going and evoked pain, while lidoaine only reduced pain-prick evoked pain. These results add to previous studies that highlight the complexity of the mechanism of neuropathic pain, and the need for carefully designing pain assessment techniques.
Finnerup et al. [42] assessed the role of lidocaine in spinal cord injury-associated neuropathic pain in a randomized control trial, again using a 5 mg/kg infusion protocol. The results confirmed previously observed effects of lidocain infusion on evoked pain in neuropathic pain patients, where lidocain infusion was found to decrease both evoked and spontaneous neuropathic pain. The authors concluded that the results are consistent with a central sodium-blocking effect of lidocain infusion.
Another interesting study was conducted by Viola et al43, which examine the long-term effect of lidocain infusion in patients with diabetic neuropathy. The investigators used the McGill Pain Questionnaire (MPQ) and found that lidocaine infusion markedly reduced both pain severity and quality at 14 and 28 days post infusion. This is a remarkable finding that highlights the long-lasting effect of lidocaine infusion in pain modulation that should be explored further in other indications.
In a retrospective multivariant analysis of patients that underwent lidocaine infusions, Carroll et al. [44] reported that both severity of pain and age of the patient influenced the likelihood of response to intravenous lidocaine infusion. They found that each point increase of pain (in an 11-point scale) increased the odds of responding to lidocaine by approximately 29%, while decade of life increased the odds by 36%. Not only are these results supportive of the role of lidocaine in severe pain, but also add age as an important characteristic of patients that are more likely respond to lidocaine, which can help guide future study designs.
Lidocaine infusion may be beneficial in other difficult to treat neuropathic syndromes such as fibromyalgia. A significant improvement was observed by Schafranski et al. [45] in the Fibromyalgia Impact Questionnaire FIQ scores, the Health Assessment Questionnaire, and visual analog scale (VAS) for pain. This improvement was sustained at 30 days after the last infusion. As for back pain, Park et al. [46] investigated the effects of intravenous lidocaine on neuropathic pain items of failed back surgery syndrome (FBSS) which the pain that occurs as result of abnormal impulse originated from the dorsal root ganglion and spinal cord. In this study, the authors demonstrated that 1 mg/kg, or 5 mg/kg of IV lidocaine, and placebo (attributed to small small size) improved pain in patients with neuropathic pain attributable to FBSS, however 5 mg/kg was significantly more effective. This study supports the lack of effect of low dose lidocaine infusion.
[47] compared intravenous lidocaine to ketorolac for the emergency department treatment of acute radicular low back pain. Patients received either 100 mg lidocaine or 30 mg ketorolac intravenously over 2 min and changes in VAS scores was evaluated at 60 min and 1 week after treatment. In this study, the authors found that intravenous lidocaine did not improve pain associated with acute radicular low back pain. The difference between findings in this study and others previously discussed is not clear, but may be related to the protocol of infusion, or the type of pain. As outlined earlier, there is generally no consistent protocol for lidocaine infusion in the literature, which might underpin the discrepancy of observed results. The aforementioned studies are summarized in Table 1 [37-39,41-43,45-54].

Evidence for use of systemic lidocaine for perioperative pain
Intravenous local anesthetic infusions have been used safely for pain control in the perioperative setting since the early 1950's [55-57]. Lidocaine given intravenously in subanesthetic doses selectively blocks pain transmission in spinal cord [58], while peripherally decreasing spontaneous neuronal discharge from A delta and C fibers thus decreasing transmission of nociceptive pain [59,60]. Lidocaine has a high hepatic extraction ratio; plasma clearance is 10 ml/kg/min in patients with normal hepatic function and blood flow. Therefore, weight dosing should take into account hepatic function and hepatic blood. from improved VAS pain scores, opioid sparing effect and decreased hospital length of stay [62]. These benefits seem to be more important in abdominal procedures where lidocaine infusion facilitated faster return of bowel function and early hospital discharge [63,64]. These benefits suggest that lidocaine infusion is effective in relieving visceral pain, which is consistent with results seen in animal visceral pain models [65] These results are less pronounced in orthopedic procedures, cardiac surgery, and tonsillectomy cases [66]. Despite extensive research on perioperative lidocaine infusion, its benefits for non-visceral procedures, dosing, timing, and duration of infusion still need to be studied through more randomized controlled trials [66]. Table 2 outlines some of the most recent randomized controlled trials using intravenous lidocaine infusion for perioperative pain [67]. These studies are summarized in Table 2 [36,64,68-89].

Evidence for use of systemic lidocaine for cancer pain
Despite advances in cancer treatment, there continues to be barriers for quality end of life pain management care for cancer patients. Prevalence of cancer pain varies from 33% to 64%, depending on disease stage and prognosis, and is usually rated as moderate to severe [90]. Because of the growing appreciation for the potential role of intravenous lidocaine infusion in treating refractory pain, lidocaine has been used to treat opioid refractory cancer pain in adults and children with very few and mostly self-limiting side effects [91,92]. However, the randomized controlled trials in this area are scant. In a recent phase two pilot randomized controlled cross over clinical trial, lidocaine infusion was successful in treating opioid refractory cancer pain with a mean duration of analgesia more than the half-life of lidocaine (9.34 days) ± 2.58 after a single infusion [93].
Intravenous lidocaine infusion is an appealing option in opioid refractory cancer pain as it is inexpensive, and easy to administer. In addition, lidocaine analgesia is no associated tolerance with repeated administration, does not depend on source of pain, can be repeated as needed, and allows for discontinuation of other analgesic with consequent drug related side effects [94]. However, lidocaine infusion is not mainstream treatment for opioid refractory cancer pain as phase 4 clinical trials are needed to establish guidelines for treatment in opioid refractory pain [93]. Lidocaine toxicity at small doses has been reported in terminally ill patients despite normal liver and renal function, suggesting altered pharmacodynamics [95]. These studies are summarized in Table 3 [93,[96][97][98].

Conclusion
In the current review, we provide a comprehensive overview of the large body of literature outlining the mechanism of action and role of lidocaine infusion in treatment of pain. Although the literature reviewed strongly supports the role of lidocaine infusion as a pain management modality, the studies reviewed vary widely in study design, patient populations, methods of pain testing, and outcomes.
Lidocaine is an amide local anesthetic with a wide range of mechanisms of action. Lidocaine, when given in a low dose intravenous infusion, successfully provides pain relief in several chronic painful conditions that have failed other treatment modalities. Lidocaine infusion is an inexpensive and relatively easily administered treatment that has been safely Kandil  used with very few side effects. Lidocaine as an infusion has opioid sparing effects, blocks sodium channels, uncouples G protein, blocks NMDA receptor, reduces circulating inflammatory cytokines, and prevents secondary hyperalgesia and central sensitization.
Lidocaine infusion has been studied extensively for perioperative pain control with contradicting outcomes. These conflicting results are likely due to the limited number of patients in each study and due to the lack of standardization of study techniques. There is a paucity of studies that have assessed differences in dose, infusion protocol and adverse effects of lidocaine administration. Lidocaine infusion has been successful in treating opioid refractory pain in cancer pain patients; however randomized controlled trials are lacking. Despite its opioid sparing effect, the role of lidocaine infusion in modulating opioid dependence and addiction in patients with chronic pain is yet to be determined. Several unanswered questions need to be addressed before lidocaine infusion can be used as a mainstream treatment; including the precise dosing regimen, infusion duration and the appropriate patient selection criteria. If proven effective, lidocaine infusion can potentially be an important tool for treatment of opioid dependence.     Table 2 Summary of randomized controlled trials of lidocaine infusion for perioperative pain.