White Paper: Outpatient Ketamine Clinics
White Paper on
OUTPATIENT KETAMINE CLINICS
Ketamine is currently being used as treatment for treatment resistant depression (TRD) and complex regional pain syndrome (CRPS) with many clinics popping up all over the country, including at least 9 clinics in Tennessee. Since there is no licensing required for these clinics, it can be hard to determine exactly how many clinics may be open and using ketamine. The problem is ketamine is not a cure and requires maintenance doses for symptoms to maintain improvement. There are currently no long-term studies on the effects of ketamine usage for longer than sedative periods. There are no policies that these clinics must be following and in accordance with. This could create issues in the future such as a new wave of addiction to ketamine when it becomes too expensive for people to keep up with at clinics, so they turn to the streets for the drug instead.
These treatments are an “off-label” use of ketamine and an alternative treatment people are using as a quick fix for their depression and pain. The problem with this is that ketamine produces CNS disruption such as inebriation, hallucinations, dissociation from the body, and dizziness. The most common side effects research has found so far are nausea, headache, and temporary increase in blood pressure 5-10% from baseline It is labeled as a schedule III-controlled substance due to its high potential for psychological dependence and low to moderate physical dependence.
Currently there are no other states that have implemented policies and regulations on the use of Ketamine in treatment of depression or complex regional pain syndrome. There have been recommendations made by the American Association of Nurse Anesthetists (AANA). They have mentioned a few guidelines they feel are important for clinics to use when opening but that does not mean all clinics follow these recommendations and implement them into their clinics. Some of these include the types of medical professionals that should be present and on site, the type of training they should have, the dosages of ketamine and infusion rates, and certification the clinic should have to be able to distribute ketamine.
There is no limit on the dosage each person gets when they go to the clinic, nor the amount of times they can receive ketamine infusions. This makes the use dangerous since ketamine effects have not been studied long term. Insurance does not currently cover outpatient ketamine infusions since it is off label.
To further augment the policies in place that are limiting opioid administration and reduce substance misuse, The Prevention Alliance of Tennessee recommends the following actions:
1. Setting a maximum dose allowed per infusion and the number of doses a person can receive per week or per month.
2. Setting criteria on the types of professionals that must be present during infusions with training in emergency resuscitation and the equipment to do so.
3. Adding Ketamine to the Controlled Substance Monitoring Database
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White Paper Summary
Substance use disorders are not a new issue in the United States, but the opioid epidemic has created a heightened awareness, serving as an opportunity to explore and look for longer-term solutions. The drug of choice is always changing with the creation and use of new and more effective drugs that come with the promise of “less side effects”. The ‘War on Drugs’ has only seemed to increase with new biotechnology and the rate at which medications are being promoted to consumers on a daily basis through various media outlets.
Implementing drug laws and new policies, especially for opioids, is an ever-increasing concern. It is important to limit the amount of substances that can be prescribed and holding prescribers accountable for grossly overprescribing of potentially addicting pharmaceutical products. It is also important to know the early warning signs of substance use disorder (SUD) and to reduce risk factors.
Ketamine is currently being used as treatment for treatment resistant depression (TRD) and complex regional pain syndrome (CRPS) with outpatient clinics being established throughout the country, including at least 9 clinics in Tennessee alone. Since there is no licensing required for these clinics, it can be hard to determine exactly how many clinics may be open and using ketamine in an outpatient setting. The problem is ketamine is not a cure and may require maintenance doses to continue to alleviate symptoms to show improvement. There are currently no long-term studies on the effects of ketamine usage for longer than sedative periods. There are no policies that these clinics must be following and in accordance with. Besides the intravenous ketamine products, there are also forms that can be taken home and used by the patient. This could create issues in the future with diversion and patient compliance to a schedule III controlled substance.
What is Ketamine?
Ketamine was introduced into clinical practice in the 1960’s and continues to be both clinically useful and scientifically fascinating, while its effects on the central nervous system remain not completely understood. Ketamine remains invaluable to the fields of anesthesiology and critical care medicine, in large part due to its ability to maintain cardiac and respiratory resistance while providing an effective dissociative anesthetic. Furthermore, there may be an emerging role in the treatment of refractory depression and Post-Traumatic Stress Disorder, Alzheimer’s, Parkinson’s, and autism.12 Intravenous Ketamine provides excellent analgesia with an impressive safety profile.
Ketamine can be given in many different forms such as intravenous (IV), intramuscular (IM), oral, rectal, topical, and nasal. The absorption rate for all of these are different and therefore,
1 Smalheiser, Neil R. “Ketamine: A Neglected Therapy for Alzheimer Disease.” Frontiers in Aging Neuroscience 11 (July 24, 2019). https://doi.org/10.3389/fnagi.2019.00186.
2 Dogan, Sigme Eva. “Ketamine Drug Trial Is Awarded $750,000 Grant.” Parkinson's Life, July 26, 2018. https://parkinsonslife.eu/ketamine-drug-trial-awarded-750000-grant-parkinsons-research/.
the amount of medication needed to produce dissociative effects is different. They also cause different side effects based on the route and amount of medication given.
Current anesthesiologists agree with the amazing effect that ketamine appears to have on depression, pain, PTSD, anxiety, and suicidal ideation. Especially with the fast-acting effect it has on those that are having suicidal thoughts or that want to die by suicide. It is a huge contrast from anti-depressants that usually take 4 to 6 weeks to work and cannot promise to be as effective as ketamine appears to be. In fact, many anti-depressants have a side effect that says they might increase suicidal thoughts and tendencies which has not been found yet in use of ketamine. Physicians recognize the problem with the limitation of current research on consequences from this type of administration. Most would recommend using other therapies such as electroconvulsive therapy (ECT) along with antidepressants before moving to such an uncertain treatment.3
To further augment policies in place that are limiting opioid administration and reduce substance misuse, the Prevention Alliance of Tennessee recommends the following actions:
1. Setting specific guidelines and criteria these facilities must follow accordingly with current accredited institution recommendations
2. Setting criteria on the types of professionals (medical and behavioral health) that must be present during infusions with training in emergency resuscitation, and the appropriate equipment to do so.
3. Adding Ketamine to the Controlled Substance Monitoring Database
Ketamine Therapy
Ketamine is a dissociative anesthetic used in surgeries and was a popular club drug. It is classified as Schedule III controlled substance by the DEA and is known for its high abuse on the streets in Japan and the United Kingdom. It has potential for moderate to low physical dependence and high potential for psychological dependence. Ketamine clinics are currently opening across the United States with 9 currently operating in the state of Tennessee. These are open and injecting ketamine without any licensure requirements or regulation. They are using the drug for treatment of depression and chronic pain which is an “off-label” treatment, but are working closely with the Ketamine Drug Task Force and the Board of Nursing to ensure safety of patients. This is all legal.4
There is cause for concern about who is running these clinics and their direct experience in working with Ketamine. The most knowledgeable would be an anesthesiologist, who would be familiar with side effects and proper dosing of the medication. Since they are treating depression and pain, it may be wise to keep a psychiatrist or clinically trained behavioral health specialist on site as well to monitor changes in mood and symptoms. A non-anesthesia boarded physician would not normally work with ketamine, and neither would a nurse in an everyday
3 Yan, Jun. “Ketamine Clinics Attract Patients Despite Unknowns.” Psychiatry Online, American Psychiatric Association Publishing, 21 Oct. 2016, psychnews.psychiatryonline.org/doi/full/10.1176/appi.pn.2016.PP10b2. 4 Hamilton, Jon. “Listen Now: Ketamine For Severe Depression: 'How Do You Not Offer This Drug To People?'.” NPR, NPR, 20 Mar. 2017, one.npr.org/?sharedMediaId=520169959:520862770.
hospital setting. This would suggest a gap in knowledge to care for patients/clients receiving these infusions.
Dosing of ketamine for anesthesia tends to be 2 mg/kg IV but can range from 1-4.5 mg/kg. In use to treat depression the doses typically range from 0.1-2 mg/kg over 40-50 minutes. Clinics typically use the same dosage but vary when it comes to the number of doses a person can receive in a week such as receiving 1 to 3 infusions a week. Another question is whether or not to limit the number of doses a person can receive over a lifetime. 5 Current research shows that there must be a mild dissociative state to produce the necessary amount of glutamate needed to stimulate brain growth to fix damaged neurons. Recommendations from the National Institute of Mental Health (NIMH) state that 0.5mg/kg can achieve this dissociation but due to age, other medications, or co-morbidities this dose may need to be increased or decreased to achieve the desired effect.
Ketamine works as an NMDA receptor antagonist.6 This means that ketamine attaches to sites of the receptor on a cell, but does not produce a response. It keeps other agonists from attaching to the receptor and producing a response such as one from pain. NMDA receptors are not only found within cells, but all over the body. There are, of course, other NMDA antagonists other than Ketamine, but these failed to demonstrate the same consistency and effectiveness in relief of symptoms.
Adverse Reactions
We know the short-term effects of IV ketamine during an infusion from its use as an anesthetic in patients. Those include hallucinations, delirium, feeling inebriated, dissociation or “out of body” experiences, dizziness, and blurred vision. The most common side effects research has found so far are nausea, headache, and temporary increase in blood pressure 5-10% from baseline. These same side effects can be experienced by patients even at lower doses of ketamine, which signals to the anesthesiologist that they should not be given a higher dosage of this drug for the next treatment.7
Those who have undergone studies using ketamine in multiple doses have found that some people have very high liver functions tests (LFTs), which treatment is then stopped and liver function eventually returns to normal. Others experience elevated hepatic enzymes, which also resulted in stopping treatments until enzymes return to normal. Unfortunately, ketamine infusions after this period tend to immediately cause elevation of hepatic enzymes or high liver function tests and must be permanently discontinued.8 It has also been found that continual
5 Henderson, Theodore A. “Practical Application of the Neuroregenerative Properties of Ketamine: Real World Treatment Experience.” Neural Regeneration Research 11.2 (2016): 195–200. PMC. Web. 3 Oct. 2018. 6 Newport, D. Jeffrey, et al. “Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression.” American Journal of Psychiatry, vol. 172, no. 10, 1 Oct. 2015, pp. 950–966., doi:10.1176/appi.ajp.2015.15040465.
7 Correll, Graeme E., et al. “Subanesthetic Ketamine Infusion Therapy: A Retrospective Analysis of a Novel Therapeutic Approach to Complex Regional Pain Syndrome.” Pain Medicine, vol. 5, no. 3, 1 Sept. 2004, pp. 263– 275., doi:10.1111/j.1526-4637.2004.04043.x.
8 Correll, Graeme E., et al. “Subanesthetic Ketamine Infusion Therapy: A Retrospective Analysis of a Novel Therapeutic Approach to Complex Regional Pain Syndrome.” Pain Medicine, vol. 5, no. 3, 1 Sept. 2004, pp. 263– 275., doi:10.1111/j.1526-4637.2004.04043.x.
usage of ketamine may lead to cystitis which results in painful hematuria, dysuria, frequency, and pain after voiding.9
Recommendations for Policies to Implement
Currently there are no other states that have implemented policies and regulations on the use of Ketamine in treatment of depression or complex regional pain syndrome in outpatient settings. There have been recommendations made by the American Association of Nurse Anesthetists (AANA).10 They have suggested a few guidelines they feel are important for clinics to use when operating, but that does not mean all clinics follow these recommendations and implement them into their practices.
In a clinical setting, there needs to be protocols and eligibility criteria to define the terms treatment resistant depression and chronic pain in order to be able to compare patient symptoms, medical diagnoses, and previous treatments to decide whether the patient can safely receive ketamine. Should there be a physician referral required before allowing treatment?
The facility needs to conduct a complete the history on the patient, medical and social, in order to determine appropriateness of this treatment for the patient as well as any history of substance misuse. In order to be sure of social history, there may be a need to drug test the patient before treatment.8 This would improve patient safety as well as prevent further misuse of drugs or reduce the potential of a new addiction. It would also help in outpatient care if the providers in the clinic worked closely with the patient’s primary care provider, pain physician, mental health provider, and/or counselor to decrease the need for duplication of services as well as reducing the potential for adverse outcomes.
There needs to be guidelines set to determine the types and number of professionals that must be present at the facility while treatments are being given: Certified Registered Nurse Anesthetist (CRNAs), Anesthetist, Physician, Mental health physician, and the team needs to be certified in Basic Life Support (BLS) and Advanced Cardiac Life Support (ACLS) with onsite emergency medications, cardiac monitors, and an Automatic External Defibrillator (AED).8 Two different types of providers should be present in order to assess the physical and mental status of the patient during and after receiving treatment to ensure safety. Those administering the medication should possess a Drug Enforcement Administration (DEA) license as well as having an active unrestricted license in the State of Tennessee.
9 Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists Regional Anesthesia & Pain Medicine 2018;43:521-546.
10 American Association of Nurse Anesthetists. Non-anesthesia Provider Procedural Sedation and Analgesia: Policy Considerations. https://www.aana.com/docs/default-source/practice-aana-com-web-documents-(all)/non anesthesia-provider-procedural-sedation-and-analgesia.pdf?sfvrsn=670049b1_4
Clinics providing ketamine infusions and treatment should be Risk Evaluation and Mitigation Strategy (REMS) certified to ensure benefits of medication outweigh the risks and should work under professional licensing boards in Tennessee.
A therapeutic dose based on weight, age, and gender should be determined with more research.8 The dose needs to be set at a maximum amount that one person can receive per kilogram of weight. Currently the standards are a “sub anesthetic dose” which has no definition. Also, what ‘maintenance’ dose is appropriate, as in less or more of the therapeutic dose. A limit on the amount of times per week or per month the person may receive additional doses. Currently anesthetists are left guessing/assuming what appropriate doses should be and range from 0.1mg/kg to 2mg/kg given over 40-50 minutes for mood disorders and up to 4 hours for pain infusions. Research has yet to determine appropriate infusion length or what length of infusion works best. Regardless, an appropriate guideline should be set in order to increase patient safety. Ketamine is easily accessible in Japan and has surpassed Heroin abuse.
Conclusion
It is obvious that more research must be completed in order to determine side effects of long term use of ketamine infusions and what conditions ketamine should be used to treat. There are some definite ethical issues at hand with the use of IV ketamine without proper information on the side effects and dosages to achieve therapeutic management with less side effects. Making ketamine accessible at home and therefore cheaper could increase the risk for potential misuse. There is a responsibility to protect the public from unregulated medical clinics that are using schedule III narcotics. Insurance currently does not cover the off-label use of Ketamine and treatments can range from $350-1000 for a single dose, but some insurance companies have begun to reimburse patients for IV treatments at approximately 10-65% of the cost. People are choosing to purchase services from clinics for treatment, but ketamine could again become a popular street drug, especially with the take home type forms of ketamine. Referrals from physicians might be something to consider requiring before being able to pursue this type of treatment, such that they must be diagnosed with CRPS or actually tried multiple treatments for depression before being allowed to try ketamine. Upkeep with ketamine therapy could also involve the use of electroconvulsive therapy (ECT) or antidepressants, which have been studied more closely and proven to have more of an effect on depression after an infusion of ketamine.11 This would be less expensive than regularly receiving doses of ketamine, but not necessarily safer as ketamine is neuroprotective and ECT is not.12
11 “Comparing Electroconvulsive Therapy and Ketamine Treatment for Adults with Major Depression That Has Not Responded to Antidepressant Medicines -- The ELEKT-D Study.” PCORI, September 7, 2019. https://www.pcori.org/research-results/2016/comparing-electroconvulsive-therapy-and-ketamine-treatment adults-major.
12 “The Neurodegenerative and Neuroprotective Effects of Ketamine.” Juvenile Bipolar Research Foundation. Accessed November 13, 2019. https://www.jbrf.org/ketamine-clinical-trial/the-neurodegenerative-and neuroprotective-effects-of-ketamine/.
Authors
Lexie Ferguson, Student Nurse, UT College of Nursing Karen Pershing, MPH, CPS II, Executive Director, Metro Drug Coalition