Ketamine: Reinventing Chronic Pain Management

For patients who respond poorly or incompletely to opioids, ketamine may be the answer.

In the middle of the past century, phencyclidine hydrochloride—called PCP or angel dust on the street—was developed to be a safe, effective anesthetic that did not cause cardiovascular and respiratory depression. However, its propensity to cause convulsions at high doses and long-lasting psychoactive side effects during emergence from anesthesia destroyed its potential.

Ketamine—a PCP derivative—was synthesized in 1963 and was tested on 20 prison volunteers in 1965. One-tenth as potent as PCP, ketamine was intended to induce anesthesia like PCP, but with greater specificity and fewer side effects.¹ The FDA approved it in 1970, and its widespread use in the Vietnam conflict theater catapulted its popularity.² Today, ketamine is used less and less in the operating suite.3 Although ketamine’s psychomimetic side effects are milder than those of PCP, they can be problematic (Table 1^2-10).

Recreational abuse has dogged ketamine since its approval. Abusers have injected, inhaled, and smoked ketamine, revealing characteristics of the drug that would otherwise remain unknown. Researchers hypothesize that abusers may develop tolerance because ketamine induces liver enzymes.¹¹ Abusers rarely experience withdrawal, instead reporting a sensation called the K-hole—a constellation of visual hallucinations, dissociation, and out-of-body, and sometimes, near-death experiences. Heavy, prolonged ketamine use can cause cognitive and psychological impairment.^4,12-15

Up to one-third of chronic ketamine abusers develop dose-dependent urinary tract symptoms within weeks to years: lower urinary tract irritation (vesicopathy), hydroureter, and hemorrhagic or ulcerative cystitis.^13,16,17 The symptom etiology remains unclear, but may be direct toxic damage, immune system activation, or the effect of unknown bacteria.^16,18 Long-term complications include hepatotoxicity (jaundice, itching, or elevated liver enzyme levels, especially in alcoholic patients) and/or cholangiopathy.^19,20 Some long-term abusers develop corneal edema.²¹ These complications reverse after cessation of ketamine use.^17,20,21 Clinically, the most common side effects of ketamine are inebriation, mental alteration, headache, hypertension, and altered liver enzymes.²²

Newer, cleaner drugs or biologics are replacing ketamine in the operative suite. Yet ketamine is finding a new place in clinical therapy. Ketamine, an N-methyl-D-aspartate (NMDA)—receptor antagonist, is becoming an option for perioperative pain management among patients with opioid tolerance, acute hyperalgesia, and chronic neuropathic pain.¹

NMDA Receptors

NMDA receptors are 1 of 3 glutamategated ion receptors. Gated by a magnesium ion, they normally open only briefly to allow calcium ions and other cations to enter the cell. Calcium activates second- messenger systems, causing neuronal hyperactivity.^1,22-24 NMDA receptors may be involved in neuronal survival and maturation, synaptic plasticity, and memory. Abnormal NMDA function may cause neurologic disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, depression, epilepsy, multiple sclerosis, Parkinson’s disease, and schizophrenia.²⁵ Unrelenting NMDA receptor excitation allows continuous calcium influx into the cell and creates hyperexcitability. This presents clinically as opioid tolerance, hyperalgesia, and allodynia.^22,26,27

Ketamine is the most potent clinically available, uncompetitive, open-channel NMDA-receptor blocker (it only works if the receptor is activated and the channel is open). Ketamine depresses the thalamus and limbic systems, preventing central nervous system centers from receiving or processing sensory input. This creates anesthesia, analgesia, and amnesia, and sometimes unpleasant psychomimetic effects or emergence phenomena.^23,28,29

Sympathetic cardiovascular stimulation caused by ketamine is unique among intravenous anesthetics: it inhibits neuronal catecholamine reuptake, thereby increasing heart rate, cardiac output, and systemic and pulmonary blood pressure.^30,31 Theoretically, ketamine use should be avoided in patients with prolonged QT syndrome.³² Ketamine inhibits neuronal serotonin reuptake, causing an emesis that is reversed by 5-HT—receptor blockers.^33,34

What Route?

To minimize adverse events associated with ketamine use, researchers are examining the use of administration routes other than intravenous. Oral ketamine, as an injectable liquid or a compounded product, is subject to hepatic first-pass metabolism and is less effective than parenteral doses. It also lacks a clear dose-response relationship.^22,35 Some study results suggest that the oral route leads to few side effects.³⁶ Topical formulations of ketamine or ketamine with other potential analgesics has been used for managing several painful conditions (eg, pelvic pain, pruritus) with mixed results.^22,37-39

Managing Pain

Ketamine use in pain management evolved from its perioperative use. Perioperative pain is expected, but may have physical or psychological consequences that delay rehabilitation and prolong hospitalization.¹ Most surgeons use opioids to treat postoperative pain and supplement with regional anesthesia, other analgesics, and adjuvant agents as needed.^1,23,40 Some patients respond poorly or incompletely to opioids; ketamine may help these patients.^26,27,41

In low doses, NMDA-receptor antagonists can provide analgesia and circumvent opioid-related tolerance, hyperalgesia, and allodynia.^10,23,40 Randomized, placebo-controlled, double-blind clinical trials (RCTs) have found that perioperative subanesthetic doses of ketamine added to opioid analgesia improved pain scores and reduced opioid consumption by approximately 30% to 50%. Ketamine was given as an intermittent low-dose intravenous bolus or a continuous infusion. It reduced opioid-related nausea and vomiting and added no additional significant adverse effects.^42,43

Ketamine can also be given with morphine patient-controlled analgesia, contributing a morphine-sparing effect. Patients with chronic neuropathic pain, opioid dependence or tolerance, and acute hyperalgesia seem to benefit more.^42,43 Low-dose ketamine administered before the surgical incision can lead to better analgesia for 24 hours after surgery.¹ Most studies report no significant increase in psychomimetic adverse effects when ketamine is added to morphine.^42,43

Sickle Cell Crisis and Chronic Noncancer Pain

Acute sickle cell disease creates severe pain with a neuropathic element. Several published guidelines recommend using opioids as first-line treatment, but some patients are unresponsive to even high opioid doses. Rapidly escalating opioid doses may induce acute tolerance and opioid-induced hyperalgesia.^29,44 Case studies (but no RCTs) indicate that adding a low-dose ketamine infusion to opioids can improve pain in sickle cell disease.⁴⁴ Usually, NMDA receptors activate continually only after a severe, sustained painful stimulus allows sufficient glutamate release. This is why ketamine may be useful as an adjuvant in several types of chronic central and peripheral neuropathic pain (Table 2^23,45,46).

Several of ketamine’s properties may prevent chronic pain from developing:

• Dampening of nociception
• Prevention or attenuation of hyperalgesia, allodynia, and tolerance
• Attenuating central sensitization and windup phenomenon from repeated noxious stimuli when previously nonpainful stimuli become exaggerated and painful^23,40

Clinicians have used short-term subanesthetic doses of ketamine to treat neuropathic pain.⁴⁵ Scheduled infusions over several days can improve pain scores in patients with chronic pain; a few studies report pain relief persisting for weeks following treatment, indicating that ketamine may be disease modifying.⁴⁶

Cancer Pain

Limited but increasing data support ketamine use in refractory cancer pain. Adding a small dose of ketamine to opioid therapy in a patient with opioid tolerance, called burst therapy, can improve pain management.^12,47 Patients on highdose opioids whose cancer pain has a neuropathic component may respond to oral ketamine.⁴⁸ Adding a small dose of ketamine to patient-controlled morphine seems to improve pain management, and some researchers are testing a ketamine mouthwash for mucositis.^49,50

Endnote

Large, well-designed RCTs are needed to confirm the analgesic role of ketamine. Most studies suggest, and experts believe, that ketamine use should be reserved for patients in whom opioids, anticonvulsants, or antidepressants have failed.^3,36 Because pain management is an off-label use for ketamine, clinicians should consult with field experts for dosing recommendations.

Ms. Wick is a visiting professor at the University of Connecticut.

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