The level of evidence for the treatment of neuropathic pain conditions with ketamine infusions was stratified based on the Oxford University Center for Evidence-Based Medicine (CEBM) criteria, which are presented in Table 1.39
Differences in reported measurements of pain make it challenging to compare pain relief achieved by different doses of ketamine over a similar period. Furthermore, it is not possible to attribute the duration of pain relief mostly to either the duration of infusion or the dose based on weight of infused ketamine.
The majority of described protocols use an infusion rate between 0.1 and 0.5 mg/kg/h.3,4,7,9–17,19,38 Three protocols describe the use of infusion rates of greater than 0.1 mg/kg/h, 2 of which required admission to an ICU setting for supportive care and monitoring, and 1 that was conducted as an outpatient also with appropriate monitoring.5,6,27 When described, the reason for choosing a certain rate is attributed to the authors’ clinical experiences or a desire to avoid unpleasant side effects. The high infusion rates in ICU settings did result in increased duration of pain relief. However, similar durations of pain relief were reported with comparably lower infusion rates given for a prolonged period of time in an inpatient and outpatient setting.3,4 The percentage of patients experiencing unpleasant side effects is reported to be comparable between different infusion rates.
Several studies have examined the use of coadministered medications for either reduction of side effects or improvement of analgesia. Several of the reviewed studies gave adjuvant medications as a standing component of a ketamine infusion protocol.4,6,10–12,18,19,24,38
Six studies focused exclusively on the use of ketamine infusions for the treatment of CRPS.3–7,26 In addition, a majority of patients analyzed in a retrospective study were diagnosed with CRPS.27 The majority of these articles report pain relief of several weeks after an infusion in an inpatient setting over 4 to 5 days. However, outpatient infusion protocols requiring multiple serial infusions also reported pain relief lasting several months in some cases.26,27 Although the general trend when all studies are considered is that longer durations provide increased duration of pain relief, there may be an optimal infusion duration of several hours beyond which no benefit is derived but the potential for side effects increases. The effective treatment of management of CRPS pain did not seem to be related to the actual dose of ketamine or the rate of infusion, with subanesthetic doses in the outpatient setting providing comparable duration of pain relief compared with higher-dose infusion protocols designed to be performed in ICU settings. The cost and required resource allocation for inpatient and ICU care are presumably greater than for outpatient management.
Three studies focused on the use of ketamine infusions for the treatment of fibromyalgia.14–16 All 3 studies utilized a relatively low dose of ketamine between 0.3 and 0.5 mg/kg administered over 10 to 30 minutes. No study reported benefits beyond the first few hours after the infusion. It is not certain whether this is because of a lack of responsiveness of fibromyalgia pain to ketamine infusions or whether a higher dose is required to produce longer lasting analgesia. The changes in pain scores after the infusion in 2 studies are encouraging and suggest that further optimization of dose and duration may provide some degree of relief.
The studies focused on the utilization of ketamine infusions to treat pain after traumatic spinal cord injury.8–10 Two of the studies utilized a relatively low dose of ketamine between 6 μg/kg and 0.4 mg/kg over 17 to 40 minutes.8,9 One protocol utilized approximately 0.2 mg/kg (based on 70 kg) over 5 hours for a total dose of 80 mg a ketamine.10 In keeping with the general trend, shorter infusion times and lower total doses of ketamine provided relief only in the immediate postinfusion phase, whereas higher doses provided relief that lasted 2 weeks.
Several other pain pathologies have been studied in well-conducted studies. However, the small number of available studies for discreet pain diagnoses does not allow for meaningful comparison.
Because of the diversity of infusion protocols and the lack of direct protocol comparisons, conducting a formal meta-analysis is not possible at this time. Definite recommendations cannot be made based on available literature. However, several relationships do emerge from inspection of the available data. These trends may provide guidance for clinicians initiating ketamine infusion therapy in their practice and to guide future optimization research.
On the basis of the available evidence, a successful ketamine infusion protocol for the treatment of chronic neuropathic pain would include several components: (1) applying the longest possible infusion duration that is logistically feasible using multiple outpatient clinic visits if necessary; (2) using a dose of ketamine between 0.1 and 0.5 mg/kg/h to avoid excessive sedation in the majority of patients; and (3) utilizing adjunct medications such as midazolam to decrease the incidence of psychomimetic side effects and possibly improve the degree of pain relief. All infusions should be done in a monitored setting with standard American Society of Anesthesiology monitors under physician supervision. Although a dose of ketamine between 0.1 and 0.5 mg/kg/h does not eliminate the need for monitoring of the risk of sedation, safe and effective use of this range has been reported in the monitored outpatient, non-ICU setting. Potential adverse outcomes, such as excessive sedation, dysphoria, and cardiovascular complications, should be monitored during and after the infusion.
There are several important caveats regarding the protocols used in prospective studies for discrete chronic neuropathic pain conditions.
Given a relative paucity of evidence in the current literature to guide ketamine infusion therapy for the treatment of various neuropathic pain conditions, such as CRPS, postherpetic neuralgia, traumatic spinal cord injury, and phantom limb pain, further well-conducted prospective comparative effectiveness studies are needed to analyze different ketamine infusion protocols in discreet neuropathic pain states. The goal of this study is to identify factors associated with better outcomes for the treatment of neuropathic pain with ketamine infusion therapy and to underscore the need for optimization through further clinical trials.
1. Domino EF. Taming the ketamine tiger. 1965. Anesthesiology. 2010;113:678684.
2. Kronenberg RH. Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration. J Pain Palliat Care Pharmacother. 2002;16:2735.
3. Sigtermans MJ, van Hilten JJ, Bauer MC, et al. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009;145:304311.
4. Schwartzman RJ, Alexander GM, Grothusen JR, et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009;147:107115.
5. Koffler SP, Hampstead BM, Irani F, et al. The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome. Arch Clin Neuropsychol. 2007;22:719729.
6. Kiefer RT, Rohr P, Ploppa A, et al. Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase II study. Pain Med. 2008;9:11731201.
7. Goldberg ME, Torjman MC, Schwartzman RJ, et al. Pharmacodynamic profiles of ketamine ®- and (S)- with 5-day inpatient infusion for the treatment of complex regional pain syndrome. Pain Physician. 2010;13:379387.
8. Eide PK, Stubhaug A, Stenehjem AE. Central dysesthesia pain after traumatic spinal cord injury is dependent on N-methyl-D-aspartate receptor activation. Neurosurgery. 1995;37:10801087.
9. Kvarnström A, Karlsten R, Quiding H, et al. The analgesic effect of intravenous ketamine and lidocaine on pain after spinal cord injury. Acta Anaesthesiol Scand. 2004;48:498506.
10. Amr YM. Multi-day low dose ketamine infusion as adjuvant to oral gabapentin in spinal cord injury related chronic pain: a prospective, randomized, double blind trial. Pain Physician. 2010;13:245249.
11. Eichenberger U, Neff F, Sveticic G, et al. Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds. Anesth Analg. 2008;106:12651273.
12. Kim YH, Lee PB, Oh TK. Is magnesium sulfate effective for pain in chronic postherpetic neuralgia patients comparing with ketamine infusion therapy? J Clin Anesth. 2015;27:296300.
13. Eide PK, Jørum E, Stubhaug A, et al. Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo. Pain. 1994;58:347354.
14. Graven-Nielsen T, Aspegren Kendall S, Henriksson KG, et al. Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain. 2000;85:483491.
15. Sörensen J, Bengtsson A, Bäckman E, et al. Pain analysis in patients with fibromyalgia. Effects of intravenous morphine, lidocaine, and ketamine. Scand J Rheumatol. 1995;24:360365.
16. Noppers I, Niesters M, Swartjes M, et al. Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: a randomized, prospective, double blind, active placebo-controlled trial. Eur J Pain. 2011;15:942949.
17. Mercadante S, Arcuri E, Tirelli W, et al. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage. 2000;20:246252.
18. Jackson K, Ashby M, Martin P, et al. “Burst” ketamine for refractory cancer pain: an open-label audit of 39 patients. J Pain Symptom Manage. 2001;22:834842.
19. Salas S, Frasca M, Planchet-Barraud B, et al. Ketamine analgesic effect by continuous intravenous infusion in refractory cancer pain: considerations about the clinical research in palliative care. J Palliat Med. 2012;15:287293.
20. Leung A, Wallace MS, Ridgeway B, et al. Concentration-effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain. Pain. 2001;91:177187.
21. Max MB, Byas-Smith MG, Gracely RH, et al. Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: a double-blind comparison to alfentanil and placebo. Clin Neuropharmacol. 1995;18:360368.
22. Felsby S, Nielsen J, Arendt-Nielsen L, et al. NMDA receptor blockade in chronic neuropathic pain: a comparison of ketamine and magnesium chloride. Pain. 1996;64:283291.
23. Jørum E, Warncke T, Stubhaug A. Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine—a double-blind, cross-over comparison with alfentanil and placebo. Pain. 2003;101:229235.
24. Tawfic QA, Faris AS, Kausalya R. The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manage. 2014;47:334340.
25. Polomano RC, Buckenmaier CC III, Kwon KH, et al. Effects of low-dose IV ketamine on peripheral and central pain from major limb injuries sustained in combat. Pain Med. 2013;14:10881100.
26. Correll GE, Maleki J, Gracely EJ, et al. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med. 2004;5:263275.
27. Patil S, Anitescu M. Efficacy of outpatient ketamine infusions in refractory chronic pain syndromes: a 5-year retrospective analysis. Pain Med. 2012;13:263269.
28. Schwartzman RJ, Grothusen J, Kiefer TR, et al. Neuropathic central pain: epidemiology, etiology, and treatment options. Arch Neurol. 2001;58:15471550.
29. Zhou QQ, Imbe H, Zou S, et al. Selective upregulation of the flip-flop splice variants of AMPA receptor subunits in the rat spinal cord after hindpaw inflammation. Brain Res Mol Brain Res. 2001;88:186193.
30. Niesters M, Khalili-Mahani N, Martini C, et al. Effect of subanesthetic ketamine on intrinsic functional brain connectivity: a placebo-controlled functional magnetic resonance imaging study in healthy male volunteers. Anesthesiology. 2012;117:868877.
31. Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-based review. Anesth Analg. 2003;97:17301739.
32. Himmelseher S, Durieux ME. Ketamine for perioperative pain management. Anesthesiology. 2005;102:211220.
33. Bell RF, Dahl JB, Moore RA, et al. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand. 2005;49:14051428.
34. Dahan A, Olofsen E, Sigtermans M, et al. Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain. Eur J Pain. 2011;15:258267.
35. Sigtermans M, Dahan A, Mooren R, et al. S(+)-ketamine effect on experimental pain and cardiac output: a population pharmacokinetic-pharmacodynamic modeling study in healthy volunteers. Anesthesiology. 2009;111:892903.
36. Herd DW, Anderson BJ, Keene NA, et al. Investigating the pharmacodynamics of ketamine in children. Paediatr Anaesth. 2008;18:3642.
37. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77:357367.
38. Kang JG, Lee CJ, Kim TH, et al. Analgesic effects of ketamine infusion therapy in Korean patients with neuropathic pain: a 2-week, open-label, uncontrolled study. Curr Ther Res Clin Exp. 2010;71:93104.
40. Eagle KA, Berger PB, Calkins H, et al.; American College of Cardiology; American Heart Association. ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). J Am Coll Cardiol. 2002;39:542553.
41. Noppers IM, Niesters M, Aarts LP, et al. Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases. Pain. 2011;152:21732178.