Sub-dissociative Dose Ketamine

Introduction

Pain is one the most common presentation to the emergency department (ED) and therefore, we should be aware of novel treatments options, adjuncts that can be used in addition to conventional therapies. Opioids are among the most commonly used analgesics in ED. Recently, a lot has been written about Low Dose Ketamine or Sub-Dissociative doses  (SDK) of ketamine to treat intractable pain or as a part of multimodal approach. 

Classically, ketamine has been used as an anesthetic agent for procedural sedation or intubation but low dose or sub- dissociative dose ketamine (SDK) may be used as an adjunct to opioids or as a single agent. SDK dosing is anywhere from 0.1-0.3 mg/kg where ketamine acts not as an anesthetic, but rather as an analgesic. Generally,  SDK does not produce many of the potentially adverse respiratory or hemodynamic effects of other analgesics, and may be used as a safe and effective alternative or adjunct to opioids. Ketamine is both hydrophilic and lipophilic which allows administration via various routes. 

It has been found that SDK lowers pain scores and has functionally equivalent efficacy to morphine for short-term analgesia in the ED. WHen used with opioids, SDK also reduces the overall dose of opioid analgesics and the need for re-dosing. 

Mechanism of action - Ketamine

After cell injury, the NMDA/glutamate receptor complex is activated in the dorsal horn of the spinal cord and these receptors are pivotal in developing hyperalgesia, allodynia and ultimately, central sensitization and wind up phenomenon (Wind-up is a frequency-dependent excitability of neurons in the dorsal horn of the spinal cord and the activation of the NMDA/glutamate receptor complex is a necessary step in the development of the wind-up phenomenon), which leads to the development of persistent and neuropathic pain as well as opioid-tolerant pain. SDK non-competitively blocks the NMDA receptors with its antihyperalgesic, antiallodynic and anti-tolerance effects. This mechanism of action of ketamine is responsible for its utility in managing a variety of acute and chronic (neuropathic, malignant, opioid-tolerant, opioid-induced hyperalgesic states) painful conditions as an adjuvant analgesic or single agent.

Ketamine undergoes extensive hepatic metabolism (via cytochrome P450 enzymes) with norketamine being an active metabolite with 1/3 of the potency of ketamine. Ninety percent of the drug is excreted in urine in the form of metabolites with 2-4% of the drug remains unchanged

In theory, patients with severe liver and renal dysfunction may have prolonged clearance and accumulation but there is no data to imply that SDK is unsafe in patients with liver or renal dysfunction

SDK Dosing:

0.1-0.3mg/kg over 15 minutes diluted in 100ml NS for short infusion - No monitoring necessary

0.15-0.2mg/kg/hr (continuous infusion): 100mg Ketamine in 100ml NS, IV pump is

necessary, titrate q30 min by 5mg until the pain is optimized or develop psycho-perceptual effects, monitoring is preferred

• Analgesic dose (0.1-0.3 mg/kg) - At these low doses, ketamine has minimal psycho-perceptual effects and works as a strong analgesic. Typically, these doses do not require monitoring.
• Recreational dose (0.2-0.5 mg/kg) ketamine works as a great analgesic but also leads to distortions of perception. 
• Dissociative dose (>0.7 mg/kg) ketamine - These doses keep them awake but unconscious. Typically this range of dose is used for PSA or intubation. 

Sitiations where SDK can be used:

Acute traumatic and non-traumatic pain

Complex regional pain syndrome

Functional abdominal pain

Migraine headache

Neuropathic and radicular pain

Sickle cell crisis

Chronic pain syndromes. 

Note: SDK does not cause respiratory depression or increase in intra-cranial or intra-ocular pressure. 

Side effects (directly related to speed of administration):

Nausea/Vomiting, Dizziness, Lightheadedness, Feeling of unreality, dysphoria

Emergence reactions - Not seen at low doses

Indications

• Acute pain: traumatic, non-traumatic, brief painful procedures, post-operative pain
• Chronic: central pain (post stroke pain), phantom pain, neuropathic pain, cancer pain
• Opioid-tolerant pain
• Opioid-induced hyperalgesic states

Contraindications

• Allergy to ketamine
• Age <2 months
• History of schizophrenia

Take Home

SDK used alone or in combination with opioids is safe and effective for the treatment of acute pain in the ED and may result in opioid sparing. Its use has been associated with relatively high rates of minor and short lived adverse side effects that can be reduced by utilizing a short-infusion of ketamine via IV of 0.3 mg/kg over 15 min.

References:

1. Johansson P, Kongstad P, Johansson A. The effect of combined treatment with morphine sulphate and low-dose ketamine in a prehospital setting. Scand J Trauma Resusc Emerg Med. 2009 Nov 27;17:61.
2. Galinski M, Dolveck F, et al. Management of severe acute pain in emergencysettings: ketamine reduces morphine consumption. Am J Emerg Med. 2007 May;25(4):385- 90
3. Ahern TL, Herring AA, Anderson ES, Madia VA, et al. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med. 2015 Feb;33(2):197-201
4. Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial Am J Emerg Med. 2015 Mar;33(3):402-8
5. Motov S, Rockoff B, Cohen V, Pushkar I, et al. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2015 Mar;22(3):251-7
6. Goltser A, Soleyman-Zomalan E, Kresch F, Motov S. Short (low-dose) ketamine infusion for managing acute pain in the ED: case-report series. Am J Emerg Med. 2015 Apr;33(4):601.e5-7.
7. Ahern TL, Herring AA, Miller S, Frazee BW. Low-Dose Ketamine Infusion for Emergency Department Patients with Severe Pain. Pain Med. 2015 Jul;16(7):1402-9.
8. Yeaman F, Meek R, Egerton-Warburton D, Rosengarten P, et al. Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients. Emerg Med Australas. 2014 Jun;26(3):237-42
9. Motov S, Mai M, Pushkar I, Likourezos A, et al. A prospective randomized, double-dummy trial comparing IV push low dose ketamine to short infusion of low dose ketamine for treatment of pain in the ED. Am J Emerg Med. 2017 Aug;35(8):1095-1100. doi: 10.1016/j.ajem.2017.03.004. Epub 2017 Mar 3.

Posted by:

              

     Lakshay Chanana

     

     ST4 Trainee

     Royal Infirmary of Edinburgh

     Department of Emergency Medicine

     Edinburgh

     Scotland

     @EMDidactic