Most pain practitioners now believe that neuroinflammation plays a role in the initiation, maintenance, and exacerbation of the chronic pain process in the nervous system—both centrally and peripherally.¹ Microglial cell activation in the brain has emerged in recent years as a key component in the development of centralized pain (central sensitization).²˒³
Regardless of ultimate drivers of chronic pain, clinicians are charged with providing relief to suffering patients. Over the past 20 years, the author has developed an outpatient intravenous (IV) pharmacologic strategy for treating unremitting pain and painful flare-ups caused by chronic pain syndromes—including migraines, headaches, and neuropathic pain.⁴ Most often, the author has employed ketamine, lidocaine, and propofol, often augmented by magnesium sulfate, as the agents of choice for treating chronic pain and headache. This article will explore the use of these agents in subanesthetic IV doses.
How They Work
Ketamine
Ketamine (2(2-chlorophenyl)-2-(methylamino)-cyclohexanone hydrochloride) has an extremely varied set of pharmacologic actions depending on the dosage that is used. It has been in clinical use since 1963. More recently, however, it has developed a reputation as a party drug under the names Special K, K, Cat Valium, Jet (Texas), Purple, Super Acid, and Vitamin K.⁵
When it is administered as prescribed, ketamine is an exceedingly safe anesthetic agent for both human and veterinary use.⁶ At subanesthetic doses, ketamine is an effective pain medication. Only a small number of clinicians, including the author, have used IV ketamine to treat migraines, headaches, and various rare pain disorders.⁷⁻⁹
Ketamine works as an antagonist to N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors (NMDARs) are crucial for neuronal communication. Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission throughout the brain. Based on their pharmacology, there are 3 main classes of glutamate-activated channels: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), kainate receptors, and NMDA receptors.¹⁰
Among iGluRs, NMDA receptors are exceptional in their high unitary conductance, high calcium (Ca²⁺) permeability, and remarkably slow gating kinetics. NMDARs form tetrameric complexes that consist of several subunits. The subunit composition of NMDARs is subject to many changes, resulting in large numbers of receptor subtypes. Each subtype has distinct pharmacological and signaling properties.¹⁰ Interest and research is growing in defining specific functions of subtypes of the glutamate receptor system in both normal and pathological conditions in the central nervous system (CNS).
In addition to migraines and other headaches, the author has used subanesthetic IV ketamine to treat many neuropathic pain disorders, including trigeminal neuralgia and facial pain, nerve entrapments, complex regional pain syndrome (CRPS), temporomandibular joint disorders (TMJD), and pelvic floor and abdominal visceral neuropathies that cause debilitating pain. Most recently, the author has utilized IV ketamine for improving treatment-resistant mood disorders (anxiety, depression, bipolar disorders, and psychosis) in extremely subanesthetic doses.¹¹
Lidocaine
IV lidocaine has been used as an analgesic agent since the 1960s. Recently, lidocaine’s mechanisms of action have been studied in more detail, emphasizing multimodal aspects that diverge from the classic sodium (Na⁺) channel blockade.¹² The classic action of lidocaine on peripheral and central Na⁺ channels depends on the presence of voltage-gated Na+ channels. Two types of channels are expressed on peripheral sensitive neurons (NaV 1.8 and NaV 1.9), while a third type of channel can be found in sensitive neurons of the sympathetic nervous system (NaV 1.7). A subtype of embryonic Na⁺ channel (NaV 1.3) has been described in damaged peripheral neurons and is associated with neuropathic pain and an increase in excitability, since peripheral hyperexcitability is partly caused by an accumulation of Na⁺ channels on the site of damage.
Lidocaine may have a different mechanism of action when treating central sensitization and peripheral or somatic pain. The development of postoperative central hyperalgesia can be reduced by blocking Na⁺ channels resistant to tetrodotoxin on nerve endings of mechanonociceptors, which are particularly sensitive to low doses of lidocaine, in the spinal cord and dorsal root ganglion. IV lidocaine (and its active metabolite, monoethylglycinexylidide) interacts with peripheral and central voltage-gated Na⁺ channels in the intracellular side of the cell membrane. It has more affinity for the opened ionic channel, which occurs during depolarization. Thus, IV lidocaine affects peripheral and central nerve endings, as mentioned.
A second mechanism of action, which diverges from the classic Na⁺ channel blockade, also has been studied. The concentration of the neurotransmitter acetylcholine increases in the cerebrospinal fluid (CSF). This might exacerbate inhibitory descending pain pathways, resulting in analgesia, probably by binding to muscarinic (M3) receptors, inhibiting glycine receptors, and releasing endogenous opioids, leading to the final analgesic effect. When lidocaine reaches the spinal cord, it reduces directly or indirectly the postsynaptic depolarization mediated by NMDA and neurokinin receptors. IV lidocaine reduces the inflammatory response to tissue ischemia. It also attenuates tissue damage induced by endothelial and vascular cytokines through a mechanism involving the release of adenosine triphosphate and potassium (K⁺) channels. Toxic doses can result in tonic-clonic seizures; these are prevented by the prior administration of IV ketamine.
Although body weight is routinely used to determine the dose of the local anesthetic to be administered, a correlation between body weight and maximal plasma concentration does not exist, making the dose calculated in mg/kg somewhat arbitrary. Nevertheless, practitioners should be aware that plasma concentrations of lidocaine and its active metabolite, monoethylglycinexylidide, have different pharmacokinetic activities. Lidocaine toxicity is more likely to manifest when its plasma concentration reaches 5 µg/mL; doses smaller than 5 mg/kg, administered slowly, under monitoring, are considered relatively safe.
The IV administration of low doses of lidocaine has been effective in the management of headaches refractory to conventional oral treatment, and the author has found this to be safe and effective as well. With pain secondary to a lesion in the CNS (central sensitization, presumably), IV lidocaine (up to 5 mg/kg) resulted in anti-allodynic and anti-hyperalgesic effects, suggesting an action on the CNS. Analgesia produced by IV lidocaine can persist when the infusion is discontinued (see Table 1). It can be tried in patients with chronic neuropathic pain who have failed oral medications. Also, it can be used to diagnose neuropathic pain and as a response test to oral sodium channel blockers.
Thus, the final analgesic action of IV lidocaine reflects the multifactorial aspect of its action, resulting from the interaction with multiple Na⁺ channels, and direct or indirect interaction with different receptors and nociceptive transmission pathways. These include M3 antagonist, glycine inhibition and reduction in the production of excitatory amino acids, reduction in the production of thromboxane A2, release of endogenous opioids and neurokinins, and actions on K⁺ channels and release of adenosine triphosphate (ATP).
As for central sensitization, it has been suggested that lidocaine works on 2 levels: a peripheral anti-hyperalgesic effect on somatic pain and a central effect on neuropathic pain, with the consequent blockade of central hyperexcitability.
Propofol
Propofol is another agent with a unique mechanism of action. A commonly used IV anesthetic, propofol is most commonly used for the induction of anesthesia. Like other intravenous anesthetics, propofol works by increasing γ-aminobutyric acid (GABA)-mediated inhibitory tone in the CNS. Propofol decreases the rate of dissociation of GABA from the receptor, thereby increasing the duration of the GABA-activated opening of the chloride channel, with resulting hyperpolarization of cell membranes.
Subanesthetically, propofol has relative specificity for subsets of GABA-A receptors. Originally, it was shown to be highly effective in eradicating intractable migraines and other headaches.¹³ Propofol has been shown to be efficacious in many chronic pain disorders. The author is currently exploring its efficacy in eliminating accompanying nausea when used in ultralow IV doses (20 to 30 mg).
Magnesium Sulfate
Magnesium sulfate (MgSO⁴) is a physiologic antagonist to calcium in many ways. The NMDA-type ionotropic glutamate receptors play a unique role in synaptic functions. It has high permeability for calcium and can be blocked in a voltage-dependent manner by endogenous Mg2+. Activity and voltage dependence of the NMDA receptor channel block by organic cations are strongly affected by competition with magnesium ions for the binding site in the channel pore.
In 1 study, NMDA receptor channel block in the presence of Mg2+ by several organic blockers was investigated.¹⁴ The dependence of the channel block is decreased, abolished, or even inverted in the presence of magnesium, and simple competition between magnesium ion and organic channel blockers might provide a general explanation of the observed effects. There may be an interaction of NMDAR channel blockers with additional binding sites.
The author is using supraphysiologic amounts of magnesium in the hope that it might have additive effects to ketamine or other anesthetic agents and thus prolong their blocking effects, although this is far from certain. The author has shown that IV MgSO⁴ can reduce or abolish migraines and other headaches, although the mechanism at the neuronal level is speculative.¹⁵
Table 1 provides an overview of the agents in subanesthetic doses that the author uses in the clinic, either singly or in various combinations, to treat a range of painful disorders, together with results of IV treatment.
How IV Therapy Is Performed: Clinical Experience
Over the past 20 years, the author has extended and amplified the use of several IV anesthetic agents in addition to the use of many so-called standard medications. Part of the mission of his practice is to provide active intervention to relieve disabling symptoms in a way that may not be possible in the community at large or in a local emergency department (ED) setting.
Whether the patient is in acute distress with a disabling migraine or other pain disorder (often both) or has had an escalating or intractable course of pain or headaches of any nature, the author’s clinic is equipped for the safe use of IV treatments, including dimmable lights in treatment rooms, IV treatment chairs, pulse oximetry monitoring, a crash cart, and ACLS/CPR trained personnel (RNs and MDs) on site.
Each treatment is preceded by an evaluation, including vital signs and a physical/neurological examination to assess the course of treatment. In many cases, the patient is in unremitting pain and has a headache, and the author is committed at that point to treat her with newer medication approaches that most likely have not been tried. In most cases, it is likely that IV therapies were not utilized at all in prior treatments, except for opioids and antinausea medications in the ED. Knowing which medications are compatible with each other in the IV solution (usually normal saline) can save much time in the treatment process strategy. Ideally,
1 agent is tried at a time, starting with low doses and based on body weight, and progressing over several days with dose escalations as tolerated by the patient or dictated by her response.
After a treatment is decided, an IV access is established (antecubital or other site) by the author or a nurse. Pulse oximetry monitoring is used for every IV or intramuscular (IM) treatment, even if the treatment is IV magnesium, valproate, dihydroergotamine, or another nonanesthetic agent. Patients are always asked to rate their pain/migraine/headache symptoms, including associated nausea, spasm, photo/phonophobia, etc, on a 0 to 10 visual analog scale (VAS) or a 0 to 11 Likert scale prior to any treatment. Symptoms are then rated approximately every 15 to 30 minutes during and after the infusion of IV medication(s).This includes any accompanying spasm or neck pain symptoms. If the patient also has anxiety and/or depression, a Hamilton Anxiety and Depression form is also filled out prior to any initial IV treatment, as well as 3 to 5 days after treatment.
Once the IV is running and medication dosages are calculated based on the patient’s weight, the medications are placed in the bag, usually in 500 to 1000 mL of normal saline. If there is significant or severe nausea at the outset, ondansetron 2 to 4 mg is given IM or IV just after placement. If the patient feels anxious or jittery, lorazepam 0.5 to 1.0 mg or midazolam 1 to 2 mg IV is given. These doses are not ordinarily headache- or pain-reducing in themselves in single doses. IV infusions last between 4 and 6 hours but can be longer. A second infusion can be done in the same day if the patient has traveled a long distance or only has a limited number of days for treatment.
Discussion
The dedicated use of IV pharmacologic agents often results in great reductions in chronic pain and headache patterns, especially in those patients who are experiencing escalating episodes or seasonal flares or are resistant to other treatment approaches. Not every treatment works for everyone, and often multiple infusion trials are needed, with dosage adjustments, to gain the benefits of the IV therapy. Slow, subanesthetic infusion of either lidocaine, ketamine, or propofol has, in the author’s hands, been more successful than one-time rapid infusions. Patients who are treated repeatedly for longer periods of time often can benefit from this slower and longer IV infusion approach.
In short, it is not a fast-food sort of issue, and patients’ expectations have to be realistic. Often, patients and their caretakers are told that a 30% to 40% reduction in pain will produce a significant gain in functionality for the patient. To maintain the beneficial effects of the IV infusion, oral prophylaxis agents may be tried. Reduction and/or removal of opioids is another desirable goal, particularly for patients with chronic daily headaches and neuropathic pain syndromes. Ketamine, low-dose naltrexone, human chorionic gonadotropin (hCG), low-dose buprenorphine, or neuronal stabilizing agents (anticonvulsants) may also be quite useful in reducing opiate usage.¹⁶ Ketamine, if successful intravenously, can be compounded in time-release capsules or in nasal spray form. Because lidocaine works on similar receptors as anticonvulsants, switching to an oral agent that blocks sodium channels may be beneficial. However, note that IV lidocaine by itself indiscriminately blocks many, if not most, sodium channels, while different oral agents are more limited in their pharmacological blockade.
It also cannot be overemphasized that establishing a restful sleep pattern is another key aspect of long-term success for the suffering patient, as well as checking baseline hormone levels. Well over 90% to 95% of patients seen for the first time at the author’s clinic have not had sleep issues addressed properly, with most reporting waking up not refreshed from sleep. It is the author’s belief that nothing will improve if restful sleep patterns are not successfully established.
It is hoped that more specific agents with similar mechanisms of action that are at least as effective as currently available agents are developed. Hopefully, these will be investigated in a double-blind, placebo-controlled manner and will greatly help lessen the use of opioids as primary agents to reduce chronic pain and headache disorders.
Conclusion
Centralized pain and headache syndromes have, by definition, altered the normal functioning, physiology, and properties of peripheral, spinal cord, and CNS components. These systems are interdependent in poorly understood ways, but neuroinflammation is thought to underlie and possibly maintain chronic painful syndromes. Regardless of the complex etiologies involved, the patient suffers from debilitating, life-altering pain, and this article attempts to describe some of the pharmacologic attempts to reduce the painful burdens, particularly emphasizing subanesthetic IV treatments in the outpatient clinic. Most often, ketamine, lidocaine, and propofol, often augmented by magnesium sulfate, are the current agents of choice for treating chronic pain and headache. This is often much more effective, convenient, and inexpensive than care in an ED setting.