A Bad Reputation

Not surprisingly, a number of you have voiced your concern about our intention to conduct a study in which ketamine, a drug known to be abused recreationally and commonly used by veterinarians, will be trialed in children.

However, the current use, safety and benefits of ketamine are much greater than you might suspect. Back in the 70’s, when the drug was first used for sedation, it very quickly developed a bad rap in this country. This was probably due to the fact that when coming out of sedation, some people experienced psychotomimetic effects such as a sense of intoxication, slowing-down, relaxation, out-of-body floating, psychedelic colors or lights, faceless people, going places, etc.[i]. Since this drug is chemically related to drugs like PCP, these side-effects caused it to quickly fall out of favor[ii].

Wide Use of Ketamine

For sedation of both children and adults, ketamine is perhaps the most widely used agent in the world. In addition to its sedation effectiveness, ketamine has some unique safety features. It does not depress the respiratory system as do regular anesthetics[iii]. Therefore, breathing apparatus is not necessary and the patient is at less risk. Additionally, once administration of the drug has stopped, its effects are very short lived. In all but a few cases[iv] out of the many hundreds of thousands1 in which ketamine has been used, both its disorienting and sedating effects have been transient and typically resolve within 30-120 minutes1. A study which included over 11,000 administrations of ketamine to children concluded that it has a wide margin of safety when used within administration standards[v].

In all recorded instances of accidental overdose, with the exception of one critically ill infant, all patients were normal on recovery and experienced no related consequences; even the 3 year boy who received 100x the intended amount[vi]. For comparison sake, a lethal dose of iv ketamine requires 400mg/kg[vii], a sedation dose of ketamine delivered through a nasal spray is approximately 3mg/kg[viii]. In our study, we intend to administer around between 1 and 2mg/kg.

These characteristics have made ketamine an ideal agent on the battlefield as well as in countries in which sophisticated hospital support is not available. Ketamine is a core medicine in the World Health Organization’s “Essential Drugs List” and is a standard technique for the American Red Cross[ix].

While the use of ketamine in this country is significantly less than elsewhere, it is nevertheless used for the following:

  • pediatric sedation in dentistry and emergency rooms
  • as an analgesic (pain reducer) for both acute and breakthrough chronic pain
  • as a bronchodilator
  • as a neuronal protective agent in prolonged seizures

Side Effects from Low-Dose Ketamine

So what about those “psychedelic-like” emergence experiences that caused so much concern? They probably derive from the fact that, rather than affect the whole brain as regular anesthesia does, ketamine works by disconnecting the central nervous system from the perception of external stimuli[x]. It has been suggested that the disorienting sensory experience occurs due to the expected and harmless reestablishment of that connection1.

Studies in which people were asked to describe their experience revealed that most of them did not find the experience unpleasant[xi]. Further, studies report that children are less concerned about these experiences than adults. This could be due to the fact that their developmental world still contains unclear boundaries between reality and fantasy[xii]. The effect is known to disappear within 2 hours.

The other symptoms associated with ketamine are fairly harmless, especially when compared to the drug’s usefulness. They include nausea, vomiting, dizziness, fatigue, blurred vision, itching, emesis (uncontrolled urination) and, as yet unreported, a cooling sensation. When used at a sedation dose, mild respiratory anomalies may occur, however these anomalies are not of clinical importance and most of them resolve without assistance[xiii].

Finally, some degree of tolerance to the drug has been observed[xiv]. This would necessitate one to increase the dose to achieve the same effect. However, this phenomenon has not been observed over the 2+ years that it has been administered to children in our pilot study. Finally, while ketamine belongs to the same class of drugs that includes PCP, ketamine does not create a physical addiction[xv].

Why Do We Want to Use Ketamine?

We hope that we have allayed some of your concerns about the safety of ketamine…particularly when it comes to children. But you are probably still wondering why we want to use it as our goal is not to sedate children.

Recently, there has been a growing interest in ketamine as a rapid and effective treatment for people with depression and bipolar disorder who are resistant to other treatments. Since 2008 we have conducted a pilot study in which we have used doses similar to those that will be given in the clinical study. We selected ketamine because it is known to reduce core body temperature and to decrease fear sensitivity: two important characteristics of Fear of Harm (FOH).

As of Dec. 2012, 60 patients (primarily children but also teens and young adults) who are characterized by FOH, and who have not responded to currently available treatments, have participated in it. All but three of the pilot study subjects experienced a remarkable reduction, and even resolution, of all the symptoms directly related to this pathway. This is not to say that there are not psychological and developmental challenges left behind that need to be addressed. But at least the neurological barrier has been lessened or removed, allowing them to work on those areas. As for psychotomimetic and other side effects, all of the pilot study participants experienced some degree of them. But for all of the participants the effects resolved within 45 minutes. Further, as each person’s treatment has continued, side effects have decreased. Read more about the Pilot Study.

In addition to our work, similar thinking has led others to conduct studies in adults with treatment resistant depression and bipolar disorder. Some of these studies preceded ours and others were concurrent. While they have used different methods to administer the ketamine, they too have arrived at similar conclusions: that ketamine provides a rapid and sustained abolition of symptoms in a large percentage of study patients who were formerly unable to find relief[xvi].

The means by which ketamine is effective for people with depression and bipolar disorder is not well understood. However, it may be due to a shift of balance in the activity between receptors on neurons (the message sending cells in your brain) that promote cell growth and receptors on neurons that shut down cell growth. Surprisingly, both of the receptors are the same type. They are called NMDA receptors. But because they are located on different parts of the cell, they have different jobs. In conditions like bipolar disorder and depression, the growth-interrupting receptors may be chronically over-activated. A line of thinking is that when a very low dose of ketamine is given, it blocks just enough of the ‘bad’ receptors while allowing most of the ‘good’ receptors to keep working. It even causes a situation in which the ‘good’ receptors can receive increased signaling[xvii]. The beneficial response is almost immediate and, through a microscope, new connections and stronger cells can be seen within hours.[xviii]

NMDA receptors are important to that pathway in the brain that we have identified as being associated with the broad range of FOH symptoms and which we believe is dysregulated. When ketamine positively affects the neurons in that pathway, all of the many downstream behaviors and symptoms associated with the pathway improve.

We also want to let you know that when ketamine is administered in very high doses, or when given in fairly high doses during a period known as the brain growth spurt, it is known to destroy neurons in an irreversible manner. Importantly however, it was also found that after the brain growth spurt, a distinct developmental period that ends at 3.5 yrs, and at doses even 100 times that which we will be using, this cell death does not occur. If you are concerned about this information, more can be found here. (all supporting citations found in links)

Given that disorders such as depression, anxiety and bipolar disorder cause a person’s neurons to lose strength and connectivity, and that low doses of ketamine improve those losses, an argument could be made that the risk of neuron degeneration is much stronger without ketamine than with it.

There is much work to be done. The study that we are about to start will provide a substantial boost to that work. In addition to measuring the effects of ketamine on this population of children, we will also gather a variety of other biological information that will contribute to future studies.

Safeguarding the Children in Our Study

The safety and well being of children is always at the forefront of our thinking. It is why we do what we do. We have demonstrated to the Federal Drug Administration that our proposed study insures that safety. Some of the ways that we will do this include the following.

  • We have chosen to err on the side of safety by using more stringent exclusion guidelines than our purposes require.
  • Among other things, a normal EKG and annual physical within 3 months prior to participation are required for inclusion
  • Vital signs of all participants will be frequently monitored by a nurse practitioner at each and every drug administration.
  • The nurse practitioner will stay with the participant, in his or her home, for the hour prior to, and at least two hours post, each administration: the time required for the normal resolution of initial drug effect.
  • As mentioned above, the dose of ketamine administered falls well within studied safety ranges. The maximum dose that any child will receive is 3mg/kg.
  • If a child and/or parent decide that they would like to leave the study, they may do so at any time for any reason.

At this time, participants of our study are limited to the metropolitan area. Subjects must be between the ages of 6 and 12 and weigh between 44 and 220 lbs. If you live in this area and would like to find out more about it, please contact our Director, Alissa Bronsteen. She can be reached at abronsteen@comcast.net.

 



[i] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

 

[ii] Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999;82(2):111-125.

Pittenger C, Sanacora G, Krystal JH. The NMDA Receptor as a Therapeutic Target in Major Depressive Disorder. CNS and Neurological Disorders – Drug Targets. 2007;6:101-115.

 

[iii] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

 

[iv] Fine J, Finestone SC. Sensory disturbances following ketamine anesthesia: recurrent hallucinations. Anesth Analg. May-Jun 1973;52(3):428-430.

Meyers EF, Charles P. Prolonged adverse reactions to ketamine in children. Anesthesiology. Jul 1978;49(1):39-40.

Perel A, Davidson JT. Recurrent hallucinations following ketamine. Anaesthesia. Oct 1976;31(8):1081-1083.

 

[v] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

 

[vi] Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. Nov 1978;133:429-435.

 

[vii] Innovative Drug Delivery Systems I. Investigator’s Brochure, v7, PMI-100/150 (intranasal ketamine 100 – 150 mg/mL)1995.

 

[viii] Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. Aug 1996;77(2):203-207.

 

[ix] Green SM, Rothrock SG, Lynch EL, et al. Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety Profile in 1,022 Cases. Annals of Emergency Medicine. 1998;31(6):688-697.

 

[x] Green SM, Roback MG, Kennedy RM, Krauss B. Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update. Ann Emerg Med. Jan 20 2011.

 

[xi] Khorramzadeh E, Lotfy AO. Personality predisposition and emergence phenomena with ketamine. Psychosomatics. 1976;17(2):94-95.

 

[xii] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

 

[xiii] Abrams R, Morrison JE, Villasenor A, Hencmann D, Da Fonseca M, Mueller W. Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Ansethsia Progress. 1993;40(3):4.

Diaz J. Intranasal ketamine preinduction of paediatric outpatients. Pediatric Anesthesia. 1997;7(4):273-278.

Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans: Psychotomimetic, Perceptual, Cognitive, and Neuroendocrine Responses. Arch Gen Psychiatry. March 1, 1994 1994;51(3):199-214.

White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

Howes MC. Ketamine for paediatric sedation/analgesia in the emergency department. Emerg Med J. May 2004;21(3):275-280.

Weksler N, Ovadia L, Muati G, Stav A. Nasal ketamine for paediatric premedication. Can J Anaesth. Feb 1993;40(2):119-121.

Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. Aug 2009;54(2):158-168 e151-154.

Green SM, Rothrock SG, Lynch EL, et al. Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety Profile in 1,022 Cases. Annals of Emergency Medicine. 1998;31(6):688-697.

Khorramzadeh E, Lotfy AO. Personality predisposition and emergence phenomena with ketamine. Psychosomatics. 1976;17(2):94-95.

 

[xiv] White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

Slogoff S, Allen GW, VWessels JV, Cheney DH. Clinical Experience with Subanesthetic Ketamine. Anesthesia and Analgesia. May-June 1974;53(3):354-358.

Byer DE, Gould ABJ. Development of Tolerance to Ketamine in an Infant Undergoing Repeated Anesthesia. Anesthesiology. 1981;54(3):255-256.

Cronin MM, Bousfield JD, Hewett EB, McLellan I, Boulton TB. Ketamine anaesthesia for radiotherapy in small children. Anaesthesia. 1972;27(2):135-142.

 

[xv] Dotson JW, Ackerman DL. Ketamine Abuse. Journal of Drug Issues. 1995;25(4):751-757.

 

[xvi] Pittenger C, Sanacora G, Krystal JH. The NMDA Receptor as a Therapeutic Target in Major Depressive Disorder. CNS and Neurological Disorders – Drug Targets. 2007;6:101-115.

Zarate CA, Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. Aug 2006;63(8):856-864.

Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. Aug 2010;67(8):793-802.

Liebrenz M, Borgeat A, Leisinger R, Stohler R. Intravenous ketamine therapy in a patient with a treatment-resistant major depression. Swiss Med Wkly. Apr 21 2007;137(15-16):234-236.

 

[xvii] Pittenger C, Sanacora G, Krystal JH. The NMDA Receptor as a Therapeutic Target in Major Depressive Disorder. CNS and Neurological Disorders – Drug Targets. 2007;6:101-115.

[xviii] Li N, Lee B, Liu R, et al.(2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science; 329:959-964.

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