2016 Practical Clinical Advances: Ketamine and Metformin

Editor’s Memo December 2016

By Forest Tennant, MD, DrPH

Last December, I wrote about 2 scientific clinical advances relevant to pain management: the recognition that circulating catecholamines control descending pain, and centralization of pain and neuroinflammation as the fundamental causes of persistent or intractable pain.

This year’s Practical Clinical Advances of 2016 recognition goes to the use of oral ketamine and metformin in chronic pain.

My criterion in citing these 2 clinical advances is quite simple: Is it a practical development that can be immediately put to work in the average pain practice? The recognition that oral ketamine and metformin reduce chronic pain is timely, as both of these agents are nonopioids that will help the country continue its efforts to find opioid alternatives in the management of chronic pain.

Ketamine and metformin are hardly new drugs, but some innovative investigators have determined how and why they belong in practical pain management.^1,2 While ketamine infusions have increasingly found merit and acceptance in management of severe chronic pain, there has been interest in whether it could be used orally in pain patients.³

Oral Ketamine

Ketamine (Ketalar, generic), a derivative of phencyclidine hydrochloride (PCP), has an extremely varied set of pharmacologic actions depending on the dosage that is used. It has been in clinical use since 1963 and was approved by the US Food and Drug Administration (FDA) in 1970. Although less popular as an anesthetic and sedative, ketamine has gained popularity when used perioperatively for pain management among patients with opioid tolerance, hyperalgesia, and chronic neuropathic pain.⁴

According to PPM Board Member John Claude Krusz, MD, PhD, “When it is administered as prescribed, ketamine is an exceedingly safe anesthetic agent for both human and veterinary use.”^5,6 At subanesthetic doses, ketamine is an effective pain medication. Only a small number of clinicians, including Dr. Krusz, have used IV ketamine to treat migraines, headaches, complex regional pain syndrome, and various rare pain disorders.^7-9

Ketamine works as an antagonist to N-methyl-D-aspartate (NMDA)-type glutamate receptors. In a randomized, placebo-controlled trial of 32 subjects, researchers in the Department of Family Medicine at the University of Washington found that oral ketamine produced pain relief and reduced opioid use without respiratory depression, psychosis, or other adverse effects.¹ The daily dosage ranged from 16 mg to 256 mg, with an average daily dose of 101 mg.

Compounding pharmacies are springing up in most sizeable communities in America, and most can now make oral ketamine. It can be ingested as a sublingual solution or tablet. Since this report, I have personally made great use of oral ketamine, and I have found that in most chronic pain patients, oral ketamine produces good pain relief and reduces the patient’s consumption of opioids. My starting dose is 25 mg twice a day, followed by an upward titration to a final dose similar to the Washington experience.

Ketamine is not without side effects and precautions. It is a well-known party drug, used under the names Special K, K, Cat Valium, Jet (Texas), Purple, Super Acid, and Vitamin K. According to the FDA, “Ketamine produces a variety of symptoms, including, but not limited to, anxiety, dysphoria, disorientation, insomnia, flashbacks, hallucinations, and psychotic episodes. Ketamine dependence and tolerance are possible following prolonged administration. A withdrawal syndrome with psychotic features has been described following discontinuation of long-term ketamine use. Therefore, ketamine should be prescribed and administered with caution.”¹⁰ Ketamine is contraindicated in patients with significant hypertension. Clinically, the most common side effects of ketamine are inebriation, mental alteration, headache, hypertension, and altered liver enzymes.⁴

We look forward to learning more about this anesthetic and how it can be safely used in clinical practice.

Metformin

Metformin is the most widely used medication for the management of blood sugar in patients with type 2 diabetes. It works by activating AMP-activated protein kinase (AMPK). Metformin has been shown to have both anti-inflammatory and antioxidant properties.¹¹ The finding that the antidiabetes drug is effective in treating chronic pain is a surprise. A number of researchers are investigating the use of this agent, and anecdotal reports from colleagues note that their pain patients do quite well on metformin.

The majority of research has been focusing on metformin’s analgesic properties in the model of the inflammatory brain. For example, metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. In a mouse model, researchers were able to show that metformin reduced the infiltration of inflammatory cells into the central nervous system (CNS), which may hold promise in the treatment of multiple sclerosis and other autoimmune disorders.¹¹

Researchers at the University of  Texas, Dallas, have demonstrated that metformin, in an animal model, significantly suppressed microglial activation. ²  The treatment successfully decreased pain hypersensitivity and cold allodynia associated with neuropathic pain, which lasted several weeks post-injection.

Metformin has also been shown to decrease the likelihood of developing nurodegenerative disease. A research group from Tulane University School of Public Health and Tropical Medicine presented a paper at the American Diabetes Association meeting showing that metformin had a protective effect on the incidence of neurodegenerative diseases in veterans. These include Alzheimer’s disease, Parkinson’s disease, dementia, and mild cognitive impairment.¹² Length of exposure was a factor. The adjusted incidence rates was the lowest among veterans who had been on metformin for 4 years or more (0.49 per 100 person-years) compared with 2.47 cases per 100 person-years among those on metformin for less than 1 year.

Other recent reports provide a rationale as to why metformin should have a key role in chronic pain states particularly those that have centralized and have neuroinflammation.^13-15 Insulin has a direct effect on CNS mitochondria. Glial cells actively absorb glucose from the blood supply that feed the CNS. Metformin crosses the blood-brain barrier and apparently has a regulatory and homeostatic effect on glial cells and neuroinflammation.

The information about metformin has not been lost on me.  In select patients with severe chronic pain, I will start a trial of metformin, 500 mg at bedtime. If there are no side effects after 10 days, I increase the dose to twice daily. I am quite impressed, to date, with metformin’s relative ease of prescribing, safety, and effectiveness in reducing pain and opioid use. There have been reports, however, about patients with diabetes on dipeptidyl peptidase-4 (DPP-4) inhibitors developing severe joint pain. We do not know whether this side effect will be a factor in the use of metformin for pain management.

Ketamine and metformin are welcome, easy-to-use additions to our prescription drug formulary because they reduce chronic pain and the need for opioids. In addition, they raise intrigue as to their basic mechanisms. One point is abundantly clear. We haven’t before considered insulin and glucose metabolism in the CNS to be a factor in chronic pain. Forcing us to think and act on this revelation is by itself worthy of the Practical Clinical Advances of 2016.

Please share your nominations for best clinical development or discovery of 2016 with us. Send your nominations to nikki.kean@verticalhealth.com.

Have a happy and healthy holiday and new year!

View Sources

 

1. Grande L, Delacruz H, Thompson M, et al. Oral ketamine for chronic pain: a 32-subject placebo-controlled trial in patients on chronic opioids. Poster presented at:  Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 417.

2. Inyang K, Szabo-Pardi T, Price T. Treatment of chronic pain: long-term effects of metformin on chronic neuropathic pain and microglial activation. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 309.

3. Rudd-Barnard G, Wallborn A, Pangarkar S, et al. A case study investigating opioid medication utilization in patients with complex regional pain syndrome before and after ketamine infusion therapy. Poster presented at: Annual Meeting of the American Pain Society; May 11-14, 2016; Austin, TX. Poster 406.

4. Wick JY. Ketamine: reinventing chronic pain management.Pharmacy Times. August 7, 2014. Available at: http://www.pharmacytimes.com/publications/issue/2014/august2014/ketamine-reinventing-chronic-pain-management?p=1. Accessed November 29, 2016.

5. Krusz JC. IV Treatment of centralized pain and headache.Pract Pain Manag. 2016;16(8)26-30.

6. Stoelting RK, Hillier SC.Pharmacology and Physiology in Anesthetic Practice. 4th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 2005.

7. Krusz JC. Intravenous treatment of chronic daily headaches in the outpatient headache clinic.Curr Pain Headache Rep. 2006;10(1):47-53.

8. Krusz JC. Difficult migraine patient.Pract Pain Manag. 2011;11(4):15.

9. Krusz JC. Traumatic brain injury: treatment of post-traumatic headaches (part 2).Pract Pain Manag. 2013;13(5):57-68.

10. Ketalar [prescribing information]. JHP Pharmaceuticals, Rochester, MI. 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016812s039lbl.pdf. Accessed November 29, 2016.

11. Nath N, Khan M, Paintlia MK, Singh I, Hoda MN, Giri S. Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis.J Immunol. 2009;182(12):8005-8014.

12. Boling D. Tulane research could help elderly veterans avoid neurodegenerative disease. Press release. June 15, 2016. Available at: https://www2.tulane.edu/publichealth/pressroom/neurodegenerative.cfm. Accessed November 29, 2016.

13. Kleinridders A, Ferris HA, Cai W, et al. Insulin action in brain regulates systemic metabolism and brain function.Diabetes. 2014;63:2232-2243.

14. DeFelice FG, Ferreira ST. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer’s disease. Diabetes. 2014;63:2262-2272.

15. Ferreira ST, Clarke JR, Bomfim TR, et al. Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease.Alzheimers Dement. 2014;10:S76-S83.