Continuing Education Activity

Acute and chronic pain remain significant health problems in the United States and worldwide. With the rise in the prevalence of many chronic degenerative diseases across the globe, the distribution and absolute numbers of persons experiencing acute and chronic pain have continued to increase. As a result, pain management has come to the forefront of the public health community. The manifestation of pain itself typically involves the peripheral and central nervous systems. Pain can be classified as nociceptive, neuropathic, or nocicplastic in origin. Nociceptive pain, also known as physiologic pain, results from activating primary nociceptive afferents by actual or potential tissue-damaging stimuli. In nociceptive pain, large nerve integrity remains preserved as sensory receptors are stimulated within visceral and somatic structures. In contrast to nociceptive pain, neuropathic pain results from direct injury or disease affecting the somatosensory system and tends to be more disabling than nociceptive pain. Neuropathic pain subdivides into peripheral (e.g., diabetic neuropathy) and central (e.g., spinal cord injury or central poststroke pain), while nociceptive pain subcategorizes into somatic or visceral (e.g., inflammatory bowel disease). This activity describes the indications, contraindications, adverse effects, and clinical benefits of ketamine for managing acute and chronic pain.

Objectives:

• Describe the mode of action of ketamine.

• Identify the indications for ketamine use in the management of pain.

• Summarize the complications of ketamine use and potential adverse reactions.

• Outline the importance of collaboration and coordination among the interprofessional care team to enhance the management of acute and chronic pain with ketamine.

Introduction

Acute and chronic pain remain important health problems in the United States and worldwide. With the rise in the prevalence of many chronic degenerative diseases across the globe, the distribution and absolute numbers of persons experiencing acute and chronic pain have continued to increase.[1] As a result, pain management has come to the forefront of the public health community.

The manifestation of pain itself typically involves the peripheral and central nervous systems. Pain can be classified as nociceptive, neuropathic, or nocicplastic in origin. Nociceptive pain, also known as physiologic pain, results from the activation of primary nociceptive afferents by actual or potential tissue-damaging stimuli. In nociceptive pain, large nerve integrity remains preserved as sensory receptors are stimulated within visceral and somatic structures. In contrast to nociceptive pain, neuropathic pain results from direct injury or disease affecting the somatosensory system and tends to be more disabling than nociceptive pain.[2] 

Neuropathic pain subdivides into peripheral (e.g., diabetic neuropathy) and central (e.g., spinal cord injury or central poststroke pain), while nociceptive pain subcategorizes into somatic or visceral (e.g., inflammatory bowel disease). Recently, the International Association for the Study of Pain added a third category to the pain classification of taxonomy for conditions that do not neatly fit into neuropathic or nociceptive categories. Nociplastic pain refers to pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage or evidence of a disease or lesion directly affecting the somatosensory system. Conditions considered to be nocicplastic pain include fibromyalgia, complex regional pain syndrome (CRPS) type I, and irritable bowel syndrome. One should keep in mind that several pain conditions, such as failed back surgery syndrome, contain elements of more than one pain category and can be classified as “mixed” pain states. In addition, conditions clearly classified as nociceptive and neuropathic often contain overlapping mechanisms with nocicplastic pain in that they involve abnormal nociceptive processing (e.g., amplified pain signals, expansion of receptive fields, decreased descending modulation). 

Pain can also categorize as acute, chronic, or a combination of these types (e.g., sickle cell crisis). Acute pain arises from a specific disease or injury, and its duration is typically self-limited. Acute pain is considered a protective biological purpose and is often associated with muscle spasms and sympathetic nervous system activation. In contrast, chronic pain may be regarded as a disease state, with its duration outlasting the normal healing time associated with disease or injury. Chronic pain may also stem from psychological states and does not serve an apparent biological purpose. Unlike the self-limited nature of acute pain, chronic pain often does not have a recognizable endpoint.

Ketamine is an N-methyl-D-aspartate (NMDA) antagonist. It was approved for use as a dissociative anesthetic agent to provide analgesia in acute pain. In recent years it has been used as a non-opiate alternative for chronic pain syndromes such as complex regional pain syndrome (CRPS), neuropathic pain, and other intractable chronic pain states. Ketamine use has also been expanded to nonanalgesic uses as well. The United States Food and Drug Association approved intranasal ketamine to treat resistant unipolar depression and suicidal ideations. Ketamine has also been used for its bronchodilatory properties in patients with severe asthma exacerbation as a temporizing measure to prevent mechanical ventilation.[3]

Ketamine use, however, is not without issues. Ketamine toxicity is a well-documented phenomenon, and hepatobiliary dysfunction has been reported with recurrent ketamine use.[4] This activity will review the indications and clinical issues to consider when using ketamine to manage acute and chronic pain. 

Function

Acute pain often follows trauma or surgery and constitutes a signal to the brain regarding the presence of noxious stimuli or ongoing tissue damage.[5] This pain signal is adaptively useful, warning the individual of danger. Thus, acute pain results directly from the outcome of a noxious event and presents as a symptom of underlying tissue damage or disease. Acute injuries, including surgery, typically manifest as nociceptive pain.[6]

Whereas acute pain symptoms dissipate with the removal of the painful stimulus, chronic pain persists beyond the useful period of the pain signal. It often continues after the initial tissue damage has resolved. Chronic pain may not be directly related to the initial tissue injury or disease condition. Instead, it may result secondarily from changes in the pain detection system, either as neuropathic pain (e.g., post-traumatic neuropathy, CRPS type II) or nocicplastic pain (e.g., CRPS type I).[2][5] Therefore, while acute pain and traumatic injury may precede the development of chronic pain, the mechanisms underlying chronic pain may differ from those implicated in acute pain.[5]

Experiencing acute or chronic pains are co-morbidities and complications, respectively, after nerve or tissue injury. As a result of this and a host of overlapping pain mechanisms at multiple sites (e.g., periphery, spinal cord, brain, and descending modulatory systems), the etiology of pain remains complex. The four most common causes of pain are cancer, osteoarthritis, rheumatoid arthritis, surgeries and non-iatrogenic trauma, and spinal problems.[6] Back pain and arthritis, in particular, are among the most commonly reported causes of chronic pain, accounting for up to one-third of all reported cases.[1][7] These conditions, along with depression, are also among the top three causes of years lost to disability. Other disease states and conditions associated with acute and chronic pain are diabetes, heart disease, depression, fibromyalgia, and asthma. There is significant overlap between chronic pain and depression in terms of co-morbidity and treatment, with many therapies effective for both indications.[8]

Ketamine Pharmacology

Ketamine is a phencyclidine derivative.[9] It is a noncompetitive antagonist of glutamate at the N-methyl-D-aspartate (NMDA) receptor-cation channel complex and leads to anesthetic effects on the central nervous system.[10] It also stimulates opioid receptors within the insular cortex, putamen, and thalamus, which confers analgesic properties to this agent. Systemically it increases sympathetic tone, which makes it the preferred agent for induction of anesthesia or analgesia in patients with hemodynamic compromise.[11] Ketamine has also been shown to have bronchodilator properties with preservation of airway reflexes and respiratory drive, which makes it a useful agent in patients with severe bronchoconstriction and when spontaneous respiration is desirable.[12][13][12]

It is important to consider the peripheral vascular effects of ketamine, especially in patients with ischemic heart disease or pulmonary hypertension, when increased sympathetic tone and increased vascular resistance may not be desirable.[14] Ketamine use in anesthesia has also been associated with hallucinations and "vivid dreams" during and after emergence from anesthesia; however, this effect can be easily minimized with the coadministration of a benzodiazepine.[15]

Intravenous ketamine has a rapid onset of less than or equal to 1 minute with a duration of action of around 10 to 20 minutes.[16] Nor-ketamine is an active metabolite of ketamine which contributes to the longer duration of anesthesia and analgesia.[16] The intramuscular ketamine effect is much slower, with an onset of around 15 to 30 minutes.[16] The duration of action is significantly longer as well due to variable absorption from muscle tissues.[17] 

Issues of Concern

Pain, in both acute and chronic forms, remains a significant health problem both in the U.S. and worldwide. The aging of the world’s population has led to an increased number of individuals experiencing both acute injuries and chronic diseases.[18] Although mortality for these conditions has decreased, their non-fatal dimensions and associated psychiatric and other comorbidities have resulted in increased years lost to disability.[19]

Among the leading causes of years lost to disability worldwide, four of the top ten low-back pain, neck pain, migraine, and musculoskeletal disorders are pain-related.[19] Globally, estimates suggest that 20% of adults suffer from chronic pain, with another 10% diagnosed each year.[1] Although some estimates suggest that 20 to 25% of the world’s population suffers from acute or chronic pain, others indicate its prevalence may be as high as 45%.[20][21] In the U.S., the Institute of Medicine estimates that chronic pain impacts 1 in 3 persons.[19] Among those with chronic pain, 15 to 25% of these patients experience pain of neuropathic etiology.[22]

Chronic pain has also been observed to have an increased frequency in women and older individuals.[5][23][24] Women present more often with headaches, abdominal pain, and widespread chronic pain. Furthermore, non-Hispanic whites and blacks report the highest rates of chronic back pain, leg, feet, arm, and hand pain, and widespread pain.[25]

Chronic pain is among the most prevalent reasons persons seek medical care, with chronic pain patients utilizing health care services almost five times more frequently than the rest of the population.[26] This increased usage is often due to ill-defined conditions, lower priority chronic disease, acute disease, and concurrent psychopathology.[27] Acute pain often presents in the postoperative period, with estimates suggesting that as many as 80% of surgical patients experience significant postsurgical pain.[28] 

It is imperative to maintain a balance between the adequate treatment of pain and preventing opiate dependence in the population. Non-opiate analgesics are, therefore, increasingly important. Ketamine, as described above, has significant advantages over opiate use in this regard, as it can provide adequate analgesia without compromising the cardiorespiratory drive. 

Indications for Ketamine Use in Pain Management 

Ketamine is indicated for managing acute pain in patients with severe pain that is not responsive to standard opioid analgesics.[29] This includes using ketamine in chronic conditions such as sickle cell disease and cancer-related pain. Its analgesic effects can be seen in subanesthetic doses and can be used in patients with a high tolerance to opiates making opioids less helpful. Ketamine may also be used preoperatively as an opiate-sparing agent, especially in patients at risk of opiate-related respiratory compromise (such as those with obstructive sleep apnea).[30] Ketamine provides an alternative to opiates for the treatment of acute pain. In a recent systematic review, low-dose ketamine was comparable to morphine in analgesic effectiveness within 60 minutes of administration, with comparable safety profiles, when used in the emergency department.[31]

Disadvantages and Adverse Side-effects of Ketamine Use

Ketamine is a potent anesthetic and analgesic agent that does not affect cardiac output, mean arterial pressure, or respiratory drive when used within recommended doses. However, caution is advised as it causes sympathetic stimulation that leads to increased myocardial oxygen demand and elevated intracranial pressure. Another important adverse effect associated with this medication is psychotropic manifestations of hallucinations, dissociative experiences, and unpleasant recall. Ketamine overdose results in loss of consciousness, respiratory depression, tachycardia, hypertension, and severe psychotropic symptoms.[32]

Clinical Significance

Summary of Consensus Guidelines on the Use of Ketamine for Acute and Chronic Pain

In 2018 the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists published the following consensus guidelines for the use of ketamine in the management of acute and chronic pain.[33][32] These are summarized as follows:

• Subanesthetic intravenous ketamine should be considered for patients undergoing procedures associated with severe postoperative pain, such as abdominal and thoracic surgery and orthopedic (limb and spine) procedures.
• Patients undergoing procedures that are expected to have mild pain levels do not benefit from ketamine infusion. 
• Ketamine should be considered for opioid-dependent/tolerant patients as an adjunct therapy to limit the use of opiates when undergoing surgery or in patients with chronic medical conditions such as those with sickle cell crises.
• When used for perioperative analgesia, ketamine bolus dose should not exceed 0.35 mg/kg, and infusion rate should not exceed 1 mg/kg/hr in non-intensive care settings. 
• Ketamine should be avoided in patients with severe or uncontrolled cardiovascular disease, severe liver disease, increased intracranial pressure, elevated intraocular pressure, pregnancy, and underlying psychiatric disease associated with psychosis.
• Evidence supporting patient-controlled analgesia (PCA) with ketamine as the sole analgesic agent postoperatively is limited. 
• For chronic regional pain syndromes (CRPS), there is moderate certainty evidence supporting the use of ketamine infusions for analgesia, which has been shown to provide pain relief for up to 12 weeks.
• For chronic pain secondary to mixed neuropathic pain, fibromyalgia, cancer pain, ischemic pain, migraine headache, and low-back pain, there is weak or no evidence to support the use of ketamine infusion for immediate pain relief.
• Excluding CRPS, there is no evidence to support using ketamine for intermediate or long-term pain relief in these situations. 
• There is low certainty evidence supporting oral ketamine as a follow-up therapy after ketamine infusions. Moreover, oral ketamine is associated with high abuse potential and should be cautiously prescribed. 
• Follow-up therapy (after intravenous ketamine infusion) with intra-nasal ketamine for breakthrough pain is supported by moderate certainty evidence and can be used in the appropriate population.  

A 2019 systematic review of a randomized controlled trial evaluating the effectiveness of intravenous ketamine for pain relief in chronic refractory pain concluded that ketamine provides significant short-term analgesic benefit in these patients, however larger, multicenter studies with longer follow-ups were needed to better assess its effectiveness and optimal treatment protocol for use in the management of chronic pain.[34]

Enhancing Healthcare Team Outcomes

The management of acute and chronic pain is best done with an interprofessional team that includes pain management clinicians (MDs, DOs, NPs, and PAs), nurses, and pharmacists. Given the recent opiate misuse epidemic, the management of pain is undergoing a reassessment. No longer is it considered the standard of care to routinely prescribe opiates to patients for all types of pain. A pain consultation should be considered for chronic pain, and patient education is highly recommended. Ketamine provides a safe and effective alternative to opiate analgesia in a multitude of clinical situations and should be considered in the appropriate clinical setting. A well-integrated interprofessional team of clinicians, nurses, and pharmacists can safely administer ketamine for analgesia in patients and curb the need for opiate-dependent analgesia. [Level 5]

Nursing, Allied Health, and Interprofessional Team Interventions

During the initial assessment, patients should be asked to describe their pain and rate its severity. The clinician should note the cause, location, quality, intensity, duration, radiation pattern, and aggravating or relieving factors for the pain experienced. In most cases, the description provided by the patient can help inform the initial pain classification. For acute pain, the determination of pain etiology is generally straightforward. However, the initial workup for determining the cause and classification of chronic pain can prove more difficult. The development of chronic pain can involve a host of biomedical and psychosocial factors; hence, the biopsychosocial model of chronic pain. As such, the evaluation of chronic pain should include screening for contributing and co-morbid conditions.[35]

Standardized self-reported instruments to evaluate pain intensity, functional abilities, beliefs and expectations, and emotional distress are currently available and should be part of an in-depth evaluation. Given ketamine’s efficacy for depression and possibly posttraumatic stress, it may relieve not only the sensory-discriminative component but also the affective-motivational component of pain. 

The physical exam should also be part of the assessment. Observation of the patient may reveal initial levels of distress or discomfort, while physical examination can be used to assess tenderness or increased sensitivity in identified areas, including the presence of allodynia and hyperalgesia. Whereas clinical assessment can be useful in the initial workup, confirmatory testing is often necessary for a presumptive diagnosis, particularly in cases when the history and physical examination suggest a possible neuropathic etiology.