Learn more about the use of subanesthetic dosages of IV agents in an outpatient headache and chronic pain clinic.
By John Claude Krusz, PhD, MD
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 (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
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.
- Adema D, Andersen A, Anderson VA, et al. PPM Centralized Pain Consensus Task Force. Clinical diagnosis of centralized pain in the age of ICD-10.Pract Pain Manag. 2015;15(3):40-48.
- Burke NN, Fan CY, Trang T. Microglia in health and pain: impact of noxious early life events.Exp Physiol. 2016;101(8):1003-1021.
- Sluka KA, Clauw DJ. Neurobiology of fibromyalgia and chronic widespread pain.Neuroscience. June 9, 2016. [Epub ahead of print].
- Krusz JC. Aggressive interventional treatment of intractable headaches in the clinic. In: Unger J.Clinics in Family Practice. Philadelphia, PA: Saunders; 2005;7:545-565.
- Drug Enforcement Administration. Office of Diversion Control Drug & Chemical Evaluation Section.Ketamine. August 2013. Available at: http://www.deadiversion.usdoj.gov/drug_chem_info/ketamine.pdf. Accessed September. 13, 2016.
- Stoelting RK, Hillier SC.Pharmacology and Physiology in Anesthetic Practice. 4th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2005.
- Krusz JC. Intravenous treatment of chronic daily headaches in the outpatient headache clinic.Curr Pain Headache Rep. 2006;10(1):47-53.
- Krusz JC. Difficult migraine patient.Pract Pain Manag. 2011;11(4):15.
- Krusz JC. Traumatic brain injury: treatment of post-traumatic headaches (part 2).Pract Pain Manag. 2013;13(5):57-68.
- Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings).CNS Neurosci Ther. 2013;19(6):370-380.
- Krusz, JC. IV ketamine efficacy in the outpatient clinic for treatment-resistant mood disorders. Poster presented at: American Neuropsychiatric Association 25th Annual Meeting; February 15-18, 2014; Seattle, WA.
- Lauretti GR. Mechanisms of analgesia of intravenous lidocaine.Rev Bras Anestesiol. 2008;58(3):280-286.
- Krusz JC, Scott V, Belanger J. Intravenous propofol: unique effectiveness in treating intractable migraine.Headache. 2000;40(3):224-230.
- Nikolaev MV, Magazanik LG, Tikhonov DB. Influence of external magnesium ions on the NMDA receptor channel block by different types of organic cations.Neuropharmacology. 2012;62(5-6):2078-2085.
- Krusz JC, Belanger J. Intravenous magnesium sulfate in the treatment of headaches. Poster presented at: American Academy of Pain Management Annual Meeting; September 1998; Atlanta,
- Krusz JC. Prophylaxis for chronic daily headache and chronic migraine with neuronal stabilizing agents.Curr Pain Headache Rep. 2002;6(6):480-485.