Diminishing the Pain

The case for ketamine with management in the ED.

Introduction

Ketamine can be used as a non-competitive N-methyl-D-aspartate (NMDA)/glutamate receptor complex antagonist. It decreases pain by diminishing central sensitization (amplification of neural signaling within the CNS that elicits pain hypersensitivity), hyperalgesia (abnormally increased sensitivity to pain) and “wind-up” phenomenon (repetitive noxious stimulation of unmyelinated C-fibers resulting in prolonged discharge of dorsal horn cells that is NMDA receptors-mediated) at the level of the spinal cord and central nervous system. [1,2]

This NMDA antagonism coupled with the potentiation of opioid receptors is primarily responsible for ketamine’s role in the management of a variety of acute painful conditions in the ED and pre-hospital arena. These anti-hyperalgesic, anti-allodynic (reduction in pain due to a stimulus that does not normally provoke pain), anti-tolerance, and anti-sensitization properties of ketamine allow the medication to be used for pain control of various chronic pain syndromes. [3, 4]

Intravenous (IV) ketamine administration in sub-dissociative (SDK, low-analgesic) doses has gained a great deal of attention for managing acute pain in pre-hospital settings and in the Emergency Department (ED). Given either as an adjunct to opioids or as a single analgesic SDK was found to be effective in pain relief in patients with acute (traumatic and non-traumatic) visceral and musculoskeletal (MSK) pain. [5-7]

The commonly used routes (IV, SQ, IN) and rarely employed (inhalation, oral) routes with their respective dosing regimens of SDK in the ED are presented in Table 1. [8-19] The frequently occurring adverse effects of SDK (dizziness, feeling unreality, nausea, sedation, and fatigue) are limiting the administration of ketamine to the ED and inpatient units under the supervision of clinicians. 

Evidence

Pre-hospital Pain Management

Ketamine administration in the pre-hospital setting is commonly used for management of traumatic painful conditions (penetrating injuries, burns, fractures, dislocations) and rescue/retrieval situations.  The IV route is the most common mode of ketamine delivery with either weight-based dosing at 0.1-0.3 mg/kg or a fixed dose at 10-20 mg. [5, 6, 20-26]

SDK administration as an adjunct to morphine resulted in greater pain relief and reduced dose of morphine in comparison to morphine alone in patients with acute MSK traumatic pain. [5,6,22] When SDK was directly compared to opioids in managing acute traumatic pain, its utilization resulted in greater analgesic efficacy than fentanyl and similar pain relief as morphine with the most common adverse effects being nausea and vomiting. [23,24]

A single study that utilized continuous ketamine infusion (initial bolus dose of 0.2 mg/kg followed by a continuous infusion of 0.2 mg/kg/hr) for patients with isolated orthopedic injuries, demonstrated good pain relief, but lacked significant reduction in morphine consumption. [25]

IN route of ketamine analgesia in the pre-hospital setting has been found effective in patients with acute musculoskeletal trauma by virtue of providing fast, effective and titratable analgesia. [26, 27]

Addition of IN ketamine at 0.75 mg/kg to nitrous oxide resulted in greater pain relief than nitrous oxide/placebo (76% of patients in combination group had more than 2-point reduction in pain at 30 minutes vs. 41% in placebo group) and slightly higher rates of minor adverse effects. [27]

A survey of 39 physicians working at a helicopter-based emergency service reported safety and efficacy of IV ketamine at 0.2-0.7 mg/kg for acute analgesia during mountain rescue with hallucinations being the most common adverse effect. [28] A recent systematic review of eight trials with 2,760 patients assessing the analgesic effects and safety profile of ketamine in comparison with other analgesics in adult patients demonstrated better pain relief, a lesser degree of nausea/vomiting, but a higher risk of agitation than opioids. [29]

Emergency Department

Acute Pain

Adult Patients

Utilization of SDK in the ED has been gaining popularity among clinicians across the country and has received an endorsement for its use in acute pain management from the American College of Emergency Physicians and American Academy of Emergency Medicine. [30, 31]

Intravenous route

Several clinical trials have evaluated the analgesic efficacy and safety of SDK as an adjunct to opioids (morphine). A randomized clinical trial of 60 adult ED patients with acute painful conditions assessed the analgesic efficacy and safety of SDK at 0.15 mg/kg, 0.3mg/kg and placebo after morphine administration. The SDK groups demonstrated greater pain relief at 120 minutes in SDK groups, but higher rates of dysphoria and dizziness with 0.3 mg/kg being more effective than 0.15 mg/kg. [32] Similarly, the addition 0.1 mg/kg to morphine showed greater analgesic response at 120 minutes post-administration, but higher rates of lightheadedness and dizziness in comparison to placebo. [33]

Numerous randomized trials have compared SDK at 0.3 mg/kg to morphine at 0.1 mg/kg via IVP in adult patients with various acute painful conditions and demonstrated similar analgesic efficacy between the two drugs at 30 minutes, but significantly higher rates of psycho-perceptual adverse effects (feeling of unreality and dizziness) in the ketamine group. [8,9, 34]. These psycho-perceptual adverse effects were even more prominent in geriatric ED patients that received ketamine at 0.3 mg/kg via IVP in a similarly designed trial. [34]

Since SDK administration via IVP route leads to higher rates of feelings of unreality and dizziness, several trials evaluated the role of short infusion over 15 minutes of SDK in adult patients with acute pain. [10, 11]

One such investigation that compared rates of adverse effects of SDK at 0.3 mg/kg given via IVP or SI demonstrated a 40% reduction in rates of feeling of unreality with preserved analgesic efficacy in the SI group. [11]

Recently, a question of whether lower dose (<0.3 mg/kg) of SDK can result in similar analgesic efficacy was put to the test. A randomized non-inferiority trial of 98 patients, randomized to either 0.15 mg/kg or 0.3 mg/kg demonstrated significant differences in pain relief and adverse effect profiles between the two dosing regimens for the short-term treatment of acute pain in the ED. [35] Finally, the systematic review of eight randomized trials with 1,191 patients comparing LDK to morphine for managing acute pain, demonstrated similar analgesic efficacy (up to 60 minutes) and a comparative safety profile between two drugs. [36]

A few trials assessed analgesic efficacy and safety of continuous ketamine infusion in management of acute pain administered either at weight-based dosing of 0.15 mg/kg/hr or a fixed dose at 20 mg/hr with an average duration of infusion of one- to four- hours and demonstrated significant pain relief with minimal rates of dizziness and fatigue. [12,13]

The utilization of continuous ketamine infusion in the ED has been endorsed by the consensus guidelines from American Society of Regional Anesthesia and Pain Medicine. [37]

Intranasal route

A prospective observational trial of 40 ED patients who received IN ketamine at 0.5-0.75 mg/kg via mucosal atomization device showed clinically significant pain relief in 88% (14). In another study of 72 patients, IN ketamine at 1mg/kg resulted in effective analgesia in 56% of study patients. [38]

When IN ketamine at 1 mg/kg was compared to 0.1 mg/kg IV morphine and to 0.15 mg/kg intramuscular morphine in patients with acute traumatic MSK injuries, it resulted in similar maximal pain reduction at 60 minutes, similar time to onset of analgesia and similar time to maximal pain reduction as opioids. [39]

More recent studies that evaluated the role of IN ketamine in management of renal colic in the ED by comparing ketamine to opioids (1mg/kg of IN Ketamine vs. 0.1 mg/kg of IV Morphine and 1 mcg/kg of IV Fentanyl) demonstrated comparable analgesic efficacy of IN ketamine to morphine in one clinical trial [40] and lack of analgesic superiority in another two. [41, 42]

It is important to emphasize that in above mentioned trials, IN Ketamine was compared to opioids, which possess inferior analgesic response in comparison to NSAID’s (particularly ketorolac). To authors’ knowledge, there are no clinical trial comparing IN ketamine to ketorolac to manage renal colic.

The one trial that compared IV Ketamine at 0.6 mg/kg dose (above SDK range) to IV ketorolac at 30 mg, demonstrated lesser degree of analgesia in ketamine group at 15- to 120-minutes post-analgesic administration with significantly higher proportion of patients experiencing dizziness and agitation. [43] Similarly, IN ketamine at 1 mg/kg failed to provide better pain relief than IV Metoclopramide or placebo in ED patients suffering from migraine headaches. [44, 45]

Subcutaneous route

Low-dose ketamine administration by SQ infusion at 0.1 mg/kg/h was compared to intravenous morphine at 0.1 mg/kg given every four hours in 40 adult patients with acute musculoskeletal trauma. Patients receiving SQ ketamine had better pain relief, were more awake and alert, had lower rates of nausea and vomiting, and did not require supplemental analgesia. [46]

Inhalation Route

Two case series with a total of 10 patients described administration of ketamine via inhalation route by using breath-actuated nebulizer in patients with acute traumatic and non-traumatic painful conditions with dosing range of 0.75mg/kg-1.5 mg/kg and demonstrated significant analgesic efficacy (an average 80% pain reduction from baseline to 120 minutes) and infrequent episodes of dizziness. [47, 48]

Oral Route

Oral formulations of ketamine are not commercially available in the ED. The parenteral formulation is given as an oral solution by using an injectable vial. In a ketamine-naive patient, oral administration of ketamine can start with a single dose of 0.5 mg/kg ketamine racemic mixture or 0.25 mg/kg S-ketamine to evaluate the effect on pain relief and the duration of effect. [49]

Doses can be increased in steps of 0.5 or 0.25 mg/kg according to the efficacy and adverse effects, respectively. The conversion from parenteral to oral administration in an equipotent dose is complex and is not solely based on a reduced bioavailability. The median conversion rate from subcutaneous to oral ketamine used in the case reports was 1:1. In all the described studies, only the racemic mixture of ketamine was administered. [49]

The evidence supporting the use of orally administered ketamine for managing acute pain in the ED is essentially non-existent. Limited case reports and case series have described the use of oral Ketamine for managing pain associated with burn wound dressing changes and post-amputation pain control. [50, 51] Very little research has been performed on the efficacy and safety of oral ketamine for pain management in the ED.

Furthermore, the data on efficacy of oral ketamine for chronic painful conditions is limited and oral ketamine may have a limited place as add-on therapy in complex chronic pain patients if other therapeutic options have failed.

Pediatric Patients

SDK has been utilized in pediatric ED patients for managing predominantly acute musculoskeletal pain by the intranasal route with good analgesic responses but with high rates of mild and transient adverse effects. [52-55]

A pilot study of 28 patients (ages 3-13) with isolated limb injuries that received IN ketamine at 1mg/kg showed significant pain relief (60% and 66% pain decrease at 30 minutes and 60 minutes post-drug administration) in 85% of patients. However, 33% of patients required rescue opioids and 100% of patients experienced dizziness and nausea. [52]

The PICHFORK (Pain in Children Fentanyl or Ketamine) trial randomized children (3-13 years of age) with isolated extremity injuries to 1.5 mcg/kg of IN fentanyl or 1 mg/kg IN ketamine and demonstrated similar pain reduction between the two groups at 30 and 60 minutes but higher rates of adverse effects in the ketamine groups (78% vs. 40%).  [52]

In a similarly designed trial where children with acute traumatic MSK pain (87 patients, ages 4-17) were randomized to 1.5 mcg of IN fentanyl or 1 mg/kg of IN ketamine, the ketamine group had a similar analgesic response as fentanyl at 20 and 30 minutes respectively, but higher rates of adverse effects (bad taste in the mouth, sleepiness, and dizziness). [54, 55]

Chronic Pain

The predominant therapeutic effects of ketamine in managing a variety of chronic painful conditions (neuropathic pain, inflammatory pain, and even cancer pain) revolve around reducing central sensitization, wind-up phenomenon, opioid tolerance and hyperalgesia by virtue of NMDA/glutamate receptor complex antagonism. [1, 2, 4]

A recently published consensus guideline on the use of IV ketamine infusions for chronic pain provided evidential support for ketamine utilization for managing chronic pain with few adverse effects, but with higher dosages and more frequent infusions resulting in greater risk for serious adverse effects. [56]

A review of 36 prospective randomized clinical trials that evaluated the analgesic efficacy of ketamine in 776 patients with chronic non-cancer pain including chronic neuropathic pain, peripheral nerve injury, complex regional pain syndrome, chronic migraine, limb ischemia, fibromyalgia, spinal cord injury and whiplash demonstrated significant pain relief during the infusion (short -term pain relief). [57]

A systematic review of 11 clinical trials assessing analgesic efficacy of ketamine in cancer-refractory pain in adult and children demonstrated that ketamine could serve as a viable option in treating such patients. The dosing regimen for ketamine infusion (IV or SQ) was from 0.05 to 0.5 mg/kg/h. [58]

The data on ketamine utilization for chronic pain in the ED, however, is sparse and limited to several case reports and case series in patients with vaso-occlusive crises of sickle cell disease by utilizing a continuous ketamine infusion with a dosing range of 0.5-2 mg/kg/hr. [59, 60]

Several clinical trials are currently being conducted in an attempt to evaluate a role of IV and IN routes of SDK in managing pain in patients with sickle cell disease. [61, 62]

Ketamine might be considered as a part of non-opioid pain management of ED patients with opioid tolerance and opioid dependence that experience acute pain or exacerbation of chronic painful conditions. [63]

Conclusion

The utilization of ketamine in a sub-dissociative dosing regimen for managing a variety of painful conditions in the ED is supported by the great body of research. Ketamine should be a part of analgesic armamentarium of ED clinicians based on its great efficacy, good safety profile and a variety of routes of administration.

ED clinicians should consider administering SDK either as an adjunct to opioid or non-opioid analgesics or as a sole agent for controlling pain of various etiologies.

Table 1. Routes and Dosing Regimens of Ketamine for Pain

Route	Dosing	Comments
Intravenous (IV): 1.      Weight-Based                 2.      Fixed 3.      Continuous Infusion	0.1-0.3 mg/kg over 15-30 minutes 15-20 mg over 15-30 minutes 0.1-0.15 mg/kg/hr	Avoid Intravenous Push Dose (Higher rates of psycho-perceptual adverse effects) Titrate infusion up by 2.5-5 mg every 30-60 minutes
Intranasal (IN)	0.7-1 mg/kg	Less invasive (than IV), rapid, titratable, and is not subject to first-pass hepatic metabolism Adult patients might require higher concentrations of ketamine Max dose per nostril-1 ml
Subcutaneous (SQ): 1.      Weight-Based 2.      Fixed 3.      Continuous Infusion	0.1-0.3 mg/kg 15-20mg 0.1-0.15 mg/kg/hr	Similar dosing regimen as the IV route Slower onset of analgesic than IV route Titrate infusion up by 2.5-5 mg every 30-60 minutes
Inhalation	0.75-1.5 mg/kg	Systemic availability of 20-40% of IV route Rapid, non-invasive, and titratable Consider using Breath-Actuated nebulizer
Oral	0.25-0.5 mg/kg	Commonly used injectable form of ketamine mg/kg Lower systemic bioavailability (16%–29% of IV route) Onset of Analgesia: 20–120 minutes May not be suitable for rapid pain control in the ED Bitter taste, consider adding sweetener

 

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