Ketamine: Reinventing Chronic Pain Management



Author: Jeannette Y. Wick, RPh, MBA, FASCP

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 12-10).

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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 223,45,46).

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 painful23,40

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


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.
1. Corssen G, Domino EF. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg. 1966;45:29-40.
2. Mathew SJ, Shah A, Lapidus K, et al. Ketamine for treatment resistant unipolar depression: current evidence. CNS Drugs. 2012;26:189-204.
3. Hardy JR, Spruyt O, Quinn SJ, Devilee LR, Currow DC. Implementing practice change in chronic cancer pain management: clinician response to a phase III study of ketamine. Intern Med J. 2014;44(6):586-591.
4. Aroni F, Iacovidou N, Dontas I, et al. Pharmacological aspects and potential new clinical applications of ketamine: reevaluation of an old drug. J Clin Pharmacol. 2009;49:957-964.
5. Morgan CJ, Curran HV; Independent Scientific Committee on Drugs. Ketamine use: a review. Addiction. 2012;107:27-38.
6. Benitez-Rosario MA, Feria M, Salinas-Martin A, et al. A retrospective comparison of the dose ratio between subcutaneous and oral ketamine. J Pain Symptom Manage. 2003;25:400-402.
7. Ryu HG, Lee CJ, Kim YT, et al. Preemptive low-dose epidural ketamine for preventing chronic postthoracotomy pain: a prospective, double-blinded, randomized, clinical trial. Clin J Pain. 2011;27:304-308.
8. Barros GA, Miot HA, Braz AM, et al. Topical (S)-ketamine for pain management of postherpetic neuralgia. An Bras Dermatol. 2012;87:504-505.
9. Chong C, Schug SA, Page-Sharp M, et al. Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: preliminary findings from a three-way randomized, crossover study. Clin Drug Investig. 2009;29:317-324.
10. Weber F, Wulf H, Gruber M, et al. S-ketamine and S-norke-tamine plasma concentrations after nasal and i.v. administration in anesthetized children. Paediatr Anaesth. 2004;14:983-988.
11. Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth. 1989;36:186-197.
12. Loftus RW, Yeager MP, Clark JA, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010;113:639-646.
13. Chen CH, Lee MH, Chen YC, et al. Ketamine-snorting associated cystitis. J Formos Med Assoc. 2011;110:787-791.
14. Schönenberg M, Reichwald U, Domes G, et al. Effects of peritraumatic ketamine medication on early and sustained posttraumatic stress symptoms in moderately injured accident victims. Psychopharmacology. 2005;182:420-425.
15. Morgan CJ, Muetzelfeldt L, Curran HV. Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study. Addiction. 2010;105:121-133.
16. Wood D, Cottrell A, Baker SC, et al. Recreational ketamine: from pleasure to pain. BJU Int. 2011;107:1881-1884.
17. Middela S, Pearce I. Ketamine-induced vesicopathy: a literature review. Int J Clin Pract. 2011;65:27-30.
18. Chu PS, Ma WK, Wong SC, et al. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int. 2008;102:1616-1622.
19. Bell RF. Ketamine for chronic noncancer pain: concerns regarding toxicity. Curr Opin Support Palliat Care. 2012;6:183-187.
20. Seto WK, Ng M, Chan P, et al. Ketamine-induced cholangiopathy: a case report. Am J Gastroenterol. 2011;106:1004-1005.
21. Wai M, Chan W, Zhang A, et al. Long-term ketamine and ketamine plus alcohol treatments produced damages in liver and kidney. Hum Exp Toxicol. 2012;31:877-886.
22. Azari P, Lindsay DR, Briones D, Clarke C, Buchheit T, Pyati S. Efficacy and safety of ketamine in patients with complex regional pain syndrome: a systematic review. CNS Drugs. 2012;26:215-228.
23. Visser E, Schug SA. The role of ketamine in pain management. Biomed Pharmacother. 2006;60:341-348.
24. Wollmuth LP, Sobolevsky AI. Structure and gating of the glutamate receptor ion channel. Trends Neurosci. 2004;27:321-328.
25. Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov. 2006;5:160-170.
26. Rodríguez-Muñoz M, Sánchez-Blázquez P, Vicente-Sánchez A, et al. The mu-opioid receptor and the NMDA receptor associate in PAG neurons: Implications in pain control. Neuro-psychopharmacology. 2012;37:338-349.
27. Orser BA, Pennefather PS, MacDonald JF. Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology. 1997;86:903-917.
28. Bhutta AT. Ketamine: a controversial drug for neonates. Semin Perinatol. 2007;31:303-308.
29. Zempsky WT, Loiselle KA, Corsi JM, et al. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain. 2010; 26:163-167.
30. Craven R. Ketamine. Anaesthesia. 2007;62:48-53.
31. Waxman K, Shoemaker WC, Lippmann M. Cardiovascular effects of anesthetic induction with ketamine. Anesth Analg. 1980;59:355-358.
32. Mikesell CE, Atkinson DE, Rachman BR. Prolonged QT syndrome and sedation: a case report and a review of the literature. Pediatr Emerg Care. 2011;27:129-131.
33. McNulty JP, Hahn K. Compounded oral ketamine. Int J Pharm Compd. 2012;16:364-368.
34. Nishimura M, Sato K. Ketamine stereoselectively inhibits rat dopamine transporter. Neurosci Lett. 1999;274:131-134.
35. Blonk MI, Koder BG, van den Bemt PM, Huygen FJ. Use of oral ketamine in chronic pain management: a review. Eur J Pain. 2010;14:466-472.
36. Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence based review. Anesth Analg. 2003;97:1730-1739.
37. Kopsky DJ, Keppel Hesselink JM, Bhaskar A, Hariton G, Romanenko V, Casale R. Analgesic effects of topical ketamine [published online May 22, 2014]. Minerva Anestesiol.
38. Poterucha TJ, Murphy SL, Rho RH, et al. Topical amitriptyline-ketamine for treatment of rectal, genital, and perineal pain and discomfort. Pain Physician. 2012;15:485-488.
39. Poterucha TJ, Murphy SL, Sandroni P, et al. Topical amitriptyline combined with topical ketamine for the management of recalcitrant localized pruritus: a retrospective pilot study. J Am Acad Dermatol. 2013;69:320-321.
40. De Kock MF, Lavand’homme PM. The clinical role of NMDA receptor antagonists for the treatment of postoperative pain. Best Pract Res Clin Anaesthesiol. 2007;21:85-98.
41. Kaneria A. Opioid-induced hyperalgesia: when pain killers make pain worse [published online June 4, 2014]. BMJ Case Rep.
42. Bell RF, Dahl JB, Moore RA, et al. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2010:CD004603.
43. Laskowski K, Stirling A, McKay WP, et al. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011;58:911-923.
44. Neri CM, Pestieau SR, Darbari DS: Low-dose ketamine as a potential adjuvant therapy for painful vaso-occlusive crises in sickle cell disease. Paediatr Anaesth. 2013;23:684-689.
45. Bell RF. Ketamine for chronic non-cancer pain. Pain. 2009;141:210-214.
46. Noppers I, Niesters M, Aarts L, et al. Ketamine for the treatment of chronic non-cancer pain. Expert Opin Pharmacother. 2010;11:2417-2429.
47. Ben-Ari A, Lewis MC, Davidson E. Chronic administration of ketamine for analgesia. J Pain Palliat Care Pharmacother. 2007;21:7-14.
48. Sear JW. Ketamine hepato-toxicity in chronic pain management: another example of unexpected toxicity or a predicted result from previous clinical and pre-clinical data? Pain. 2011;152:1946-1947.
49. White MC, Hommers C, Parry S, Stoddart PA. Pain management in 100 episodes of severe mucositis in children. Paediatr Anaesth. 2011;21:411-416.
50. Ryan AJ, Lin F, Atayee RS. Ketamine mouthwash for mucositis pain. J Palliat Med. 2009;12:989-991.