Ketamine for chronic pain

Patients with complex and chronic pain conditions may experience that conventional pain management with for example opioids is insufficient for pain relief. Ketamine is mainly used in anaesthesia, but in lower doses may also be used for pain management in the acute setting.

Question

What clinical evidence exists for the treatment of low-dose intravenous ketamine for chronic pain conditions?

 

Table with identified studies

Table 1. Overviews over systematic reviews
Included studies Population Outcome
Bell and Kalso 2018 [1]
18 systematic reviews Several populations: chronic noncancer pain, refractory cancer pain, opioid-resistant pain in palliative care, postoperative pain (chronic and acute) Several assessment tools (pain intensity, overall pain level, pain relief, opioid consumption, adverse effects)
Authors' conclusion:
“The evidence for the use of ketamine in palliative care is limited, and it is not possible to recommend any specific treatment regimen. However, despite the limited evidence, a trial of low dose ketamine, adjuvant to opioid (morphine), may be warranted in refractory cancer pain or pain in palliative care. […] The evidence regarding ketamine for chronic noncancer pain is extremely limited, and there is a lack of safety data concerning long-term or repeated treatments. Importantly, there seems to be no strong evidence for the current widespread use of intermittent ketamine infusions.”
Jonkman et al 2017 [2]
29 systematic reviews, including 8 systematic reviews on chronic pain, including any route of ketamine administration Several populations: chronic non-cancer pain, cancer pain, prevention of chronic pain following surgery, acute postoperative pain, acute non-postoperative pain Several assessment tools (analgesic effect, analgesic duration, adverse effects, pain in motion, risk of developing persistent pain)
Authors' conclusion:
“Ketamine treatment is most effective for relief of postoperative pain, causing reduced opioid consumption. In contrast, for most other indications (that is, acute pain in the emergency department, prevention of persistent postoperative pain, cancer pain, and chronic non-cancer pain), the efficacy of ketamine is limited. Ketamine’s lack of analgesic effect was associated with an increase in side effects, including schizotypical effects.”
   
Connolly et al 2015 [3]
6 systematic reviews, 5 RCT, 13 observational studies, 21 case reports, including any route of ketamine administration. Includes evidence levels Complex Regional Pain Syndrome (CRPS) Several assessment tools (pain relief, pain intensity, NRS, VAS, MPQ, numerical pain intensity, movement parameters, sensory testing)
Authors' conclusion:
“There is no high quality evidence available evaluating the efficacy of ketamine for CRPS and all manuscripts examined in this review were of moderate to low quality. Therefore, we conclude there is currently only weak evidence supporting the efficacy of ketamine for CRPS, yet there is clearly a rationale for definitive study.”
“Based on the literature identified and the extent of evidence found for ketamine for CRPS, we find the evidence to date to be inconclusive. The quality of the research to date is low, in small “n” studies, with methodological flaws; thus there we conclude there is only weak evidence for the efficacy of ketamine for CRPS, and it cannot be considered a first line option. Nonetheless, CRPS is a significant clinical problem with limited therapeutic options, and therefore, any intervention able to produce improvements should be studied properly, and our review suggests subanesthetic dose ketamine holds promise. There is a critical need for “high quality, randomized, controlled trials with larger numbers of patients and standardized, clinically relevant routes of administration”
O’Connell et al 2013 [4]
19 systematic reviews, including 1 SR on iv ketamine CPRS Pain (NRS)
Authors' conclusion:
“GRADE quality judgement: There was low quality evidence (evidence from RCTs: downgrade twice for sample size) that a course of intravenous ketamine may be effective for CRPS-related pain. The effects did not appear to be sustained beyond four to 11 weeks post-treatment.”
   

 

Table 2. Systematic reviews over several pain conditions
Included studies Population Outcome
Michelet et al 2018 [5]
6 RCT
All studies on ketamine, 4 studies on iv infusion. Includes risk of bias assessment, meta-analysis and evidence grading.
Chronic non-cancer pain [Several populations: CPRS, neuropathic pain] Pain score (VAS, NRS, Brief Pain Inventory)
Authors' conclusion:
“Results of this meta-analysis found moderate evidence suggesting the efficacy of ketamine during chronic pain. Further studies are warranted to conclude about the effect of ketamine during chronic pain conditions and to determine optimal administration regimes of this agent during this condition.”
Maher et al 2017 [6]
26 studies:
11 RCT, 4 prospective observational, 4 retrospective studies. All studies on iv ketamine, multiple infusion protocols. Includes evidence levels.
Neuropathic pain [Several populations: Complex Regional Pain Syndrome (CPRS), fibromyalgia, traumatic spinal cord injury Pain relief (several assessment tools)
Authors' conclusion:
“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.”
Noppers et al 2010 [7]
36 RCT
All studies on ketamine, 21 studies on iv infusion.
Chronic non-cancer pain [Several populations: CPRS, nerve injury, chronic neuropathic pain, periphreal neuropathic pain, neuropathic pain from spinal cord injury, post-traumatic pain, post-nerve injury, whiplash, postherpeutic neuralgia, painful limb ischemia, arterio-sclerosis of lower limb, chronic migraine, fibromyalgia, phantom limb Analgesic effect
Authors' conclusion:
“While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing longterm (months) relief of chronic pain. […] Other administration modes are less effective in causing long-term pain relief. There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR.”

 

Table 3. Systematic reviews over specific pain conditions
Abbreviations:
CLI = Chronic limb ischemia; CRPS = Complex regional pain syndrome; IV = Intravenous; MPQ = McGill Pain Questionnaire; NMDA = N‐methyl D‐aspartate; NMDAR = N‐methyl D‐aspartate receptor; NRS = Numerical rating scale; PLP = Phantom limb pain; PO = Per oral; PPSP = Persistent post-surgery pain; RCT = Randomized controlled trial; VAS = Visual analogue scale
Included studies Population Outcome
Zhao et al 2018 [8]
15 studies:
RCT, cohort studies. All ketamine iv infusions, includes meta-analysis.
Complex Regional Pain Syndrome (CRPS) Pain relief (several assessment tools), pain relief event rate (percentage of patients who achieved 30% or higher pain relief)
Authors' conclusion:
“Our findings suggested that ketamine infusion can provide clinically effective pain relief in short term for less than 3 months. However, because of the high heterogeneity of the included studies and publication bias, additional random controlled trials and standardized multicenter studies are needed to confirm this conclusion. Furthermore, studies are needed to prove long-term efficacy of ketamine infusion in the treatment of CRPS.”
Azari et al 2012 [9]
3 RCT, 7 observational studies, 9 case studies. All ketamine studies, multiple routes of administration. Includes risk of bias assessment and evidence levels. Complex Regional Pain Syndrome (CRPS) Pain relief (several assessment tools)
Authors' conclusion:
”In aggregate, the data available reveal ketamine as a promising treatment for CRPS. […] The current level of evidence is 2B (i.e. weak recommendation, moderate-quality evidence) for the use of ketamine in the treatment of CRPS pain. We do not have sufficient evidence to recommend routine use of ketamine in CRPS. Within the context of this limited evidence for use of ketamine, there are limited data about the optimal dose, route and timing of admini-stration. Although ketamine demonstrates promise for safe and effective use in the treatment of CRPS, the need for large, well designed, randomized controlled trials is evident.”
Humble et al 2015 [10]
32 studies.
[Several interventions: including 6 studies on ketamine, iv or epidural).
Post-surgical pain (after amputation, thoracotomy or mastectomy) Pain (VAS, NRS, verbal rating score), pain at rest, pain at movement, sensory testing
Authors' conclusion:
”Ketamine was not effective at reducing chronic pain. […] This systematic review was limited to amputation, mastectomy and thoracotomy because these operations are considered to […] be associated with a combination of nociceptive and neuropathic symptoms and carry a high risk of chronic pain. If it is accepted that the severity of acute pain is correlated with the risk of developing chronic pain, then it follows that the perioperative period is a logical target for interventions aimed at reducing or preventing the phenomenon.”
McNicol et al 2014 [11]
17 RCT
All ketamine studies, administered peri-operatively via any route.
Includes risk of bias assessment and meta-analysis.
Persistant post-surgery pain (PPSP) Risk of developing PPSP
Authors' conclusion:
”In this meta-analysis of all eligible studies, combining intravenous and epidural administration, ketamine did not provide a significant reduction of PPSP at 3 and 6 months . In common with systematic reviews of short-term effects of ketamine on acute pain outcomes, the study data from our review of outcomes at 3 months or later are heterogeneous and suggest efficacy of intravenous ketamine only in comparison with placebo in preventing PPSP at 3 and 6 months. There was no evidence to support epidural ketamine administration for PPSP prevention.”
Alviar et al 2016 [12]
14 studies [Several interventions, including 2 studies on ketamine Phantom Limb Pain Pain intensity, sleep, depression/mood, function, quality of life, adverse events, satisfaction with treatment, withdrawals
Authors' conclusion:
”The N‐methyl D‐aspartate (NMDA) receptor antagonists ketamine (versus placebo; versus calcitonin) and dextromethorphan (versus placebo), but not memantine, had analgesic effects. The adverse events of ketamine were more serious than placebo and calcitonin and included loss of consciousness, sedation, hallucinations, hearing and position impairment, and insobriety.”
McCormick et al 2014 [13]
27 studies.
[Several interventions: including 5 RCT on ketamine, iv or epidural administration. Includes evidence levels.
Phantom Limb Pain Pain
Authors' conclusion:
”Level 2 evidence exists for the perioperative use of ketamine (IV or epidural), which non-competitively blocks NMDA receptors, for acute pain reduction but little for a prolonged duration of treatment effect [124–128]. Currently, the best evidence (level 2) exists for the use of IV ketamine and IV morphine perioperatively for short-term treatment of PLP and PO morphine for an intermediate to long-term treatment effect (8 weeks to 1 year).”
Laoire et al 2017 [14]
6 RCT, including 2 RCT on ketamine Ischemic pain. Patients with non-reconstructable critical limb ischemia Pain (VAS, Brief Pain Inventory)
Authors' conclusion:
“Two RCTs comparing ketamine with normal saline and morphine sulfate showed significantly reduced pain scores in the intervention groups. […] However, the side effect profile continues to be the limiting factor in its use. The overall benefit of ketamine to treat pain secondary to CLI is, therefore, still questionable.”
Bredlau et al 2013 [15]
5 randomized, double-blind, controlled trials, 6 prospective uncontrolled trials, 0 randomized controlled trials in children. All ketamine studies, administered via any route. 1 RCT on iv infusion. Chronic cancer pain (adults and children) Pain relief (several assessment tools)
Authors' conclusion:
”Despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain. […] In children and adults with cancer pain that has not responded adequately to standard therapy, the literature supports considering ketamine as an adjuvant therapy.
Recommended ketamine infusion dosages are from 0.05 to 0.5 mg/kg/h (intravenous or subcutaneous). Recommended oral dosages of ketamine are 0.2-0.5 mg/kg/dose two to three times daily with a maximum of 50 mg/dose three times daily .”

 

References

  1. Bell RF; Kalso EA. Ketamine for pain management. PAIN Reports: 2018; 3(5):e674.
  2. Jonkman K, Dahan A, van de Donk T, Aarts L, Niesters M, van Velzen M. Ketamine for pain. F1000Res. 2017;6. pii: F1000 Faculty Rev-1711.
  3. Connolly SB, Prager JP, Harden RN. A systematic review of ketamine for complex regional pain syndrome. Pain Med. 2015;16(5):943-69.
  4. O'Connell NE1, Wand BM, McAuley J, Marston L, Moseley GL. Interventions for treating pain and disability in adults with complex regional pain syndrome. Cochrane Database Syst Rev. 2013;(4):CD009416.
  5. Michelet D, Brasher C, Horlin AL, Bellon M, Julien-Marsollier F, Vacher T, Pontone S, Dahmani S. Ketamine for chronic non-cancer pain: A meta-analysis and trial sequential analysis of randomized controlled trials. Eur J Pain. 2018;22(4):632-646.
  6. Maher DP, Chen L, Mao J. Intravenous Ketamine Infusions for Neuropathic Pain Management: A Promising Therapy in Need of Optimization. Anesth Analg. 2017;124(2):661-674.
  7. Noppers I, Niesters M, Aarts L, Smith T, Sarton E, Dahan A. Ketamine for the treatment of chronic non-cancer pain. Expert Opin Pharmacother. 2010;11(14):2417-29.
  8. Zhao J, Wang Y, Wang D. The Effect of Ketamine Infusion in the Treatment of Complex Regional Pain Syndrome: a Systemic Review and Meta-analysis. Curr Pain Headache Rep. 2018;22(2):12.
  9. 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(3):215-28.
  10.  Humble SR, Dalton AJ, Li L. A systematic review of therapeutic interventions to reduce acute and chronic post-surgical pain after amputation, thoracotomy or mastectomy. Eur J Pain. 2015;19(4):451-65.
  11.  McNicol ED, Schumann R, Haroutounian S. A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain. Acta Anaesthesiol Scand. 2014;58(10):1199-213.
  12.  Alviar MJM, Hale T, Lim‐Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochrane Database of Systematic Reviews 2016;10. CD006380.
  13. McCormick Z1, Chang-Chien G, Marshall B, Huang M, Harden RN. Phantom limb pain: a systematic neuroanatomical-based review of pharmacologic treatment. Pain Med. 2014;15(2):292-305.
  14. Laoire ÁN, Murtagh FEM. Systematic review of pharmacological therapies for the management of ischaemic pain in patients with non-reconstructable critical limb ischaemia. BMJ Support Palliat Care. 2017;pii: bmjspcare-2017-001359.
  15. Bredlau AL, Thakur R, Korones DN, Dworkin RH. Ketamine for pain in adults and children with cancer: a systematic review and synthesis of the literature. Pain Med. 2013;14(10):1505-17.

SBU Enquiry Service consists of systematic literature searches to highlight studies that can address questions received by the SBU Enquiry Service from Swedish healthcare or social service providers. Relevant references are compiled by an SBU staff member, in consultation with an external expert when needed. The quality of the studies identified is not systematically reviewed.

Contact SBU: registrator@sbu.se
Report no: ut201837
Registration no: SBU 2018/556

Literature search

Project group

Malin Höistad, Sally Saad, Irene Edebert and Pernilla Östlund at SBU.

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