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Care Partners Protocol:
Ketamine Dosing in Pain Control
Original Date: January 2016
Clinical Use and Background of Ketamine
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to
be effective in the treatment of opiate-resistant pain syndrome of different
etiologies and is being increasingly used in the palliative care setting due to its
opiate-sparing effects. Certain pain syndromes, such as cancer pain and neuropathic
pain, either from a central or peripheral etiology are amongst the most challenging
and difficult to effectively treat. Treatment of these conditions more commonly
requires high-dose opiates that may be associated with an increase in significant
side effects thereby precluding adequate analgesia. Ketamine is used in palliative
care settings primarily for neuropathic pain which is unresponsive or poor
responsive to first- line analgesics (which may include one or more of opioid drug,
NSAID, TCA, or anticonvulsant). 1 It is strongly recommended to use a trial of
intravenous ketamine infusion before oral ketamine administration for a faster
titration and monitoring of side effects. This should be ideally done in a monitored
setting such as an intensive or palliative care unit. On the other hand, patients in the
palliative care setting, especially patients at the end of their lives, may also benefit
from a trial of oral ketamine, even if an intravenous trial is not feasible.2
Evidence supports the beneficial use of Ketamine in the following pain
types/syndromes:
 Neuropathic pain
 Phantom pain
 Complex pain syndrome
 Any pain syndrome with the triad of:
 Allodynia
 Hyperalgesia
 Prolongation of pain response
 Ischemic pain (including peripheral vascular disease)3
Indications for Use
 Opioid Intolerance
 Opioid Toxicity
 Pain poorly responsive to opioids
 Pain crisis
Patients should be given the appropriate conventional analgesics before ketamine.

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Benefits Of ketamine use
 Opioid sparing effects lead to both reduced opioid requirements and opioid
associated side effects
 May prevent opioid tolerance and reduce central sensitization and
hyperalgesia
 May have anti-inflammatory effects
 Excellent analgesia with limited respiratory depression
 Rapid onset and minimal side effects at sub-anesthetic doses 4
Pharmacokinetics of oral and intravenous ketamine
Oral ketamine undergoes extensive first –pass metabolism in the liver. As a result,
bioavailability of oral ketamine ranges from 16.5% to 24% depending on the dosage
form used. The T1/2 of oral ketamine is reported to be 5.1 to 5.5 hours, which does
not differ from the T1/2 of ketamine administered intravenously. After oral
administration, peak plasma concentrations are achieved in approximately 30
minutes. Oral ketamine is primarily metabolized to norketamine by CYP 3A4 and
CYP 2B6. Norketamine is an active metabolite, though less potent than ketamine. 10
Formulation/ Administration
Ketamine is supplied as an injection solution in 50 mg/ml and 100mg/ml multi-dose
vials. The solution can be given PO/SL/SQ/IM/IV/PR/ Intranasal. The medication
has a bitter taste that can be disguised with flavoring when given orally. Flavored
solution for oral consumption needs to be administered immediately after
preparation. Ketamine needs to be protected from light .5
Dose Adjustments
Dose reduction is advised in patients with hepatic impairment due to prolonged
duration of action. In renal failure dose increases may be considered.6 An important
point in regards to other opioids and their doses when used concomitantly with
ketamine: after intravenous infusion of ketamine, reduce opiate by 25%-30% daily
once adequate analgesia has been reached.2
(Note that the comment about possibly having to increase the dose in renal failure
originated from the 2007 Pain Physician journal article “Ketamine: An Introduction
for the Pain and Palliative Medicine Physician” by Thomasz Okon. Ketamine dosing
and metabolism is a highly controversial topic. It is up to the provider to decide,
whether in the case of renal failure, ketamine should be dose adjusted.
Drug Precautions

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As a result of NMDA receptor antagonism, ketamine may decrease or even reverse
opioid tolerance that can lead to an improved response to opioids and increased risk
of developing unwanted side effects such as sedation and respiratory depression.
Therefore proper opioid dose adjustment is imperative. Due to the fact that
ketamine may enhance the effectiveness of the prescribed opioid, careful titration of
ketamine as well as the opioid is a must if both are used concomitantly.3 If ketamine
is used with methadone, be alert to the possibility of opioid toxicity developing over
several days as a consequence of the long and variable half-life of methadone.1
Common Drug Interactions
Ketamine may affect the metabolism of warfarin, phenytoin, theophylline
(tachycardia and seizures), and levothyroxine (monitor for hypertension,
tachycardia).
Potential side effects of ketamine
1. Altered central nervous system function: vivid dreams or nightmares, anxiety,
hallucinations, dizziness, and paranoid ideations. These effects can be minimized
or treated by concurrent use of haloperidol or a benzodiazepine.7
2. Gastrointestinal adverse effects associated with oral ketamine include nausea,
vomiting, loss of appetite, and abdominal pain.2
3. Hypertension, tachycardia.8
4. Diplopia
5. Excessive salivation.1
6. Patients receiving doses over 400 mg/24 hours can have symptoms of urinary
frequency, urge incontinence, dysuria, and/or hematuria. If a patient on
ketamine experiences urinary symptoms with no evidence of bacterial infection
consider discontinuation.1
Eligibility Criteria for Ketamine Use
1. Pain above 6 (scale 0-10, zero defines no pain; 10 defines severe, excruciating)
despite the adequate dose escalation of opioids.
2. Oral witnessed informed consent.
3. Age above 18 years.9
Contraindications
Absolute:
 Presence of seizures (epilepsy)
 Increased intracranial pressure
 Patient under 18
 Allergy to ketamine
Relative:
 Hypertension – systolic > 160 mmHg
 Severe cardiac failure

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 Previous cerebrovascular accidents / Severe neurological impairment.10
 Severe psychiatric disorders, although primary evidence exists that ketamine
can be an effective depression treatment.10
Implementation
 Initiate ketamine only if ordered by a palliative care physician
 Review patient’s opioid drug regimen, if patient is on long acting opioids
switch to short acting.1
 Nursing staff administering ketamine has documented knowledge and skills
for administering sedation and anesthetic agents.3
 Prior to initiating therapy, it is important to discuss with the patient and
their family that prolonged IV Ketamine use in an outpatient setting has not
been fully clinically researched as safe or effective and is an off-label
medication application.13
 Test dose can be given: recommended test doses range from 5 mg
intravenously or subcutaneously to 20 mg orally; close observation and
monitoring of a patient is imperative. Prophylactic haloperidol or a
benzodiazepine can be given for the test dose.10
Dosage Regimen for Ketamine Use Inpatient Setting
Initial IV ketamine administration
Start:
Initiate at 0.5 mg/kg IV over 4 - 6 hours (average dose 30 mg based on a 60 kg
patient, i.e. 5 mg/hour x 6 hours).6,10
1 mg of lorazepam at infusion initiation and every 3 hours x 2 subsequent doses prn
for psychotomimetic side effects. Alternatively, 2 mg of haloperidol can be
given. Glycopyrrolate 0.2-0.3 mg subcutaneous every 6 hours prn can be given for
excessive salivation or lacrimation.6
Assess:
Psychotomimetic side effects and vitals every 1hour x 3, and pain intensity every 2-
3 hours.
o Stop infusion if heart rate > 110 bpm, systolic blood pressure increase by
more than 25% baseline, sustained RR <7, agitation or severe, intolerable
psychotomimetic side effects present.6
If pain improved by 50% or more during the initial infusion continue with
intravenous infusion at a total dose of 1.5 mg/kg/day for 48 to 72 hours, then
convert 1:1 to subcutaneous three times daily.6

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NOTE: An important point in regards to other opioids and their doses when used
concomitantly with ketamine: after intravenous infusion of ketamine, reduce opiate
by 25%-30% daily, once adequate analgesia has been reached.2
If pain not improved and no severe side effects, start 2 mg/kg infusion over the
next 12 hours (effectively doubling the initial dose). Before the next round of
titration a five-elimination half-life is suggested (i.e. 25 to 28 hours). It is
recommended that the total daily dose be limited to 500 mg/day to avoid
psychotomimetic adverse effects.6,10
If pain recurs, titrate upward by 50%-100% every 24 hours.2 Consider stopping
Ketamine if no improvement at ketamine levels of 700 mg/24 hrs.14
Conversion from intravenous to oral route: Preferentially, intravenous infusion of
ketamine is preferred for at least 48 to 72 hours before oral administration. 1:1
conversion is suggested.6,10 See the note below. The dose might need to be adjusted
based on individual needs.
Note: The range in effective dosages of orally administered ketamine varies
extensively between patients. Variability in hepatic metabolism resulting in an
increased or reduced bioavailability and variance in plasma levels of norketamine
can lead to intra-individual variability.11 Oral ketamine remains a third or fourth
line treatment option in patients with intractable cancer-pain or neuropathy. At
issue is the lack of randomized controlled trials investigating efficacy and side effect
profile of oral ketamine especially as it relates to the inter and intra-individual
variability in drug metabolism.2
Oral ketamine administration without first giving IV ketamine
First oral dose of 0.5 mg/kg/day given during a medical visit. Ketamine is
administered three times daily. Pre-assessment and monitoring procedure
followed in the same manner as outlined during IV administration. If patient
tolerates oral ketamine with no adverse reactions, recommended titration of 5 mg
with each intake stepped up 15-20 mg/day. At the end of the first week evaluate
efficacy and adverse effects. Effective dose reached in one month. If no improvement
at 3 mg/kg/day, stop the retreatment. Continue the treatment for 1-3 months and
after that consider progressive withdrawal. The suggested maximum de-escalation
is 15-20 mg/3 days (5 mg for each intake).15
Nursing Considerations
 Close monitoring of the patient is crucial. Monitor respiratory rate, heart
rate, blood pressure, pain score and sedation score.14

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 Patient should be checked for psychotomimetic side effects from ketamine
that include emergence phenomena, a floating sensation, vivid dreams,
hallucinations, delirium, and excess sedation.12
 Patients also should be checked for opioid toxicity when opioids are not
reduced during ketamine administration.12
 Low doses of ketamine reduce the need for opioids and the respiratory
depression and airway compromise may occur when opioid doses are not
decreased. Check for airway compromise and respiratory depression even
though respiratory depression with low doses of ketamine is uncommon.12
 Patients should be warned that ketamine in oral form tastes bitter.
Subcutaneous injections could cause irritation, therefore sites should be
rotated frequently.12
 Patient may experience psychotomimetic effects of parenteral administration
of ketamine, including hypotension, excessive sedation, nausea, vomiting,
excessive salivation, and apnea.12
References
1. Specialist Guidelines for Using Ketamine. Wales (UK): All Gwent Palliative
Medicine Consultants Group. 2013 Oct [cited 2016 January 10]. Available from
http://www.wales.nhs.uk/sites3/Documents/814/Ketamine-
SpecialistGuidelinesOnUse.pdf
2. Soto E, Stewart D, Manners A, et al. Oral Ketamine in the Palliative Care Setting: A
Review of the Literature and case Report of a Patient with Neurofibromatosis
Type 1 and Glomus Tumor-Associated Complex Regional Pain Syndrome. Am J
Hosp Palliat Care. 2012 June [cited 2016 January 7]; 29(4):308-317. Available
from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239997/
3. Community Protocol for Ketamine Administration. Kitchener (ON): Waterloo
Wellington Palliative Care. Available from http://hpcconnection.ca/wp-
content/uploads/2015/03/22916_Ketamine_Protocol_W.pdf
4. Davis, J. Why Ketamine? Hospice and Palliative Care Center. 2011 May [cited
2016 January 7]. Available from
http://hospicecarecenter.org/sites/default/files/education/Why%20Ketamine-
handouts.pdf
5. Ketamine In: Lexi-Drugs Online. Hudson (OH): Lexi-Comp; 1978-2016 [cited
2016 January 15] Available from: http://online.lexi.com with subscription.
6. Okon, T. Ketamine: An Introduction for the Pain and Palliative Medicine
Physician. Pain Physician. 2007 Apr [cited 2016 January 9]; 10:493-500.
Available from http://www.painphysicianjournal.com/linkout?issn=1533-
3159&vol=10&page=493
7. Mercandante S, Arcuri E, Tirelli W, et al. Analgesic Effect of Intravenous
Ketamine in Cancer Patients on Morphine Therapy: A Randomized, Controlled,
Double-Blind, Crossover, Double-Dose Study. Journal of Pain and Sympton
Management. 2000 Oct [cited 2016 January 11]; 20(4):246-252. Available from
http://www.sciencedirect.com/science/article/pii/S0885392400001949

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8. Jackson K, Ashby M, Martin P, et al. “Burst” Ketamine for Refractory Cancer Pain:
An Open-Label Audit of 39 Patients. Journal of Pain and Symptom Management.
2001 October [cited 2016 January 8]; 22(4):834-842. Available from
http://www.jpsmjournal.com/article/S0885-3924(01)00340-2/pdf
9. Lossignol D, Obils-Porti M, Body J. Successful Use of Ketamin for Intractable
Cancer Pain. Support Care Cancer. 2004 October [cited 2016 January 9]; 13:188-
193. Available from http://www.ncbi.nlm.nih.gov/pubmed/15480820
10. Prommer, E. Ketamine for Pain: An Update of Uses in Palliative Care. Journal of
Palliative Medicine. 2012 April [cited 2016 January 11]; 15(4):474-83. Available
from http://www.ncbi.nlm.nih.gov/pubmed/22500483
11. Blonk M, Koder B, Van den Bemt P, et al. Use of Oral Ketamine in Chronic Pain
Management: A Review. European Journal of Pain. 2009 September [cited 2016
January 9]; 14:466-472. Available from http://rsds.org/wp-
content/uploads/2015/02/Blonk_Koder_etal.pdf
12. Campbell-Fleming J, Williams A. The Use of Ketamine as Adjuvant Therapy to
Control Severe Pain. Clinical Journal of Oncology Nursing. 2008 February [cited
2016 January 10];12(1):102-107. Available from
https://www.researchgate.net/publication/5592809_The_Use_of_Ketamine_as_
Adjuvant_Therapy_to_Control_Severe_Pain
13. Webster L, Walker M. Safety and Efficacy of Prolonged Outpatient Ketamine
Infusions for Neuropathic Pain. American Journal of Therapeutics. 2006
July/August [cited 2016 January 10]; 13(4);300-305. Available from
http://rsds.wpengine.com/wp-content/uploads/2014/12/2015Safety-and-
efficacy-of-prolonged-outpatient-ketamine-infusions-for-neuropathic-pain.pdf
14. Fitzgibbon E, Viola R. Parenteral Ketamine as an Analgesic Adjuvant for Severe
Pain: Development and Retrospective Audit of a Protocol for a Palliative Care
Unit. Journal of Palliative Medicine. 2005 Feb [cited 2016 January 12]; 8(1):49-
57. Available from http://www.ncbi.nlm.nih.gov/pubmed/15662173
15. Marchetti F, Coutaux A, Bellanger A, et al. Efficacy and Safety of Oral Ketamine
for the Relief of Intractable Chronic Pain: A Retrospective Five Year Study of 51
Patients. European Journal of Pain. 2015 [cited 2016 January 15]; 19(2015);984-
993. Available from
http://onlinelibrary.wiley.com/doi/10.1002/ejp.624/abstract;jsessionid=8A95
D0A4E20CD4FD526F4C4329BBD1D2.f04t02