Ketamine is an old drug, and has been in clinical practice for nearly 40 years, but we should not forget this drug for the treatment of neuropathic pain, and we should not be too conservative exploring ketamine as a treatment for otherwise treatment refractory neuropathic pain patients. Ketamine can be used in various ways, as infusions, oral, rectal, intranasal and transdermal. 

As an analgesic drug, doses used are much lower compared to dose-ranges used in anesthesiological practices. Furthermore, the whole story of S-ketamine being less psychoiactive compared to R-ketamine is based on old literature, with very small groups of patients, non-relaible biological read outs, such as the EEG and animal studies with very little relevance for the human species.  

Ketamine in neuropathic pain anno 2011: still hot! 

In chronic pain the N-methyl-D-aspartic acid receptor has been described to be upregulated in the spinal cord, a state known as central sensitization. Logically ketamine, as an antagonist of this receptor has been on the radarscreen of painspecialists for many years as a putative treatment for difficult to treat pain states.  

Anno 2010 ketamine is still frequently mentioned as a relevant analgesic for the treatment of severe neuropathic pain syndromes, such as central pain due to cord lesions, as well as for other chronic pain indications such as Complex Regional Pain Syndrome Type 1. ^[1][2][3]

The effects of ketamine in models of neuropathic pain is already been known for decades. ^[4][5][6] Controlled clinical trials in patients suffering from neuropathic pain syndromes started more than 15 years ago ^[7][8]

Sind 1994 various articles, based on case reports, pilot studies and clinical trials have documented the value of ketamine in the treatment of neuropathic pain states. We mention a few to show the variety in administration forms of ketamine and clinical syndromes. 

1. Local bolus of low dose ketamine was effective in decreasing allodynia in a scar after operation. ^[8]
2. IM injection of a bolus ketamine decreased chronical postoperative pain in orofacial surgery. ^[10]
3. Long term subcutanious infusions of ketamine decreased pain in neuropathic cancerpain ^[11] 
4. Repeated short time ketamine infusions reduced pain in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans. ^[12]
5. Patients with difficult to treat, neuropathic pain syndromes were managed succesfully with low dose parenteral ketamine. Treatment started at a low dose, i.e., 40-60 mg over 24 hours, and patients were converted to oral ketamine at doses 30 to 40% of the previous parenteral dose.^[13]
6. Ketamine injection fluid taken orally relieved neuropathic treatment refractory pain ^[14]
7. Ketamine oral (4 times 50 mg/day) significantly reduced pain in postamputation stump pain and oral ketamine also had some efficacy in CRPS type 1 (case). ^[15][16]
8. 30 mg of ketamine given oral to 32 patients, five times daily was effective enough and side-effects were the following: 22% of patients reported dizziness, 25% of patients complained about drowsiness and 19% of patients reported dry mouth during oral therapy. ^[17]
9. Various patients have used doses ranging from 100-500 mg day for over 1 year duration and have reported improvements in pain and decreased use of analgesics in neuropathic pain states ^[18] Two year oral treatment has been reported too. ^[19]
10. Oral ketamine low dose was effective in the treatment refractory chronic neuropathic pain of spinal origin.^[20]
11. Ketamine ointment was effective in CRPS type 1 ^[21]
12. Oral ketamine was effective in central pain after stroke in a case report ^[22]
13. Ketamine IV in a patient-controlled analgesic delivery system was effective in spinal cord neuropathic pain.^[23]
14. Prolonged (8 weeks) analgesic ketamine infusions were safe and effective for the small group of nonresponsive neuropathic pain patients in ambulatory outpatients. ^[24]
15. In a small double blind pilot trial ketamine reduced neuropathic phantom pain ^[25] 
16. Ketamine given chronicaly for 4 years had analgsic effects in post-herpetic neuropathic pain. ^[26][27]
17. Topically ketamine gel showed relevant effects in neuropathic pain. ^[28]
18. A lozenge containing 25 mg of ketamine under development ^[29]
19. Ketamine tablets for oral use have been developed by Japanese researchers. ^[30]
20. (S)-ketamine 0.2mg/kg and 0.4mg/kg intranasal administerd lead to peak plasma concentrations of 27.7+/-5.9ng/ml and 34.3+/-22.2ng/ml at 13.8+/-4. 6-8min after application, and pain scores decreased significantly in both groups with minimal pain at 60 min after drug administration ^[31] 
21. Ketamine use by the oral, intranasal, transdermal, rectal, and subcutaneous routes has been reported with analgesic efficacy in treating neuropathic pain. ^[32][33]

Ketamine is and remains a highly interesting drug for the treatment of therapy resistant neuropathic pain syndromes. Not only can it be administered via various routes, long term treatment has been described and recently Dutch anesthesiologists reported that relative short courses of infusion can trigger long periods of decreased pain. Dahan et al in Leiden showed that CRPS-1 patients with severe pain treated for four days with a continuous infusion of low-dose S-ketamine had a clinically relevant reduction in pain lasting for up to 11 weeks. ^[2]

Jan M. Keppel Hesselink, MD, PhD, May 2010, revision november 2011

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