What is the role of oral ketamine in pain management?
Acute and chronic pain are common conditions with over half of American adults experiencing pain in the past 3 months and about 1 in 5 adults with chronic pain.1,2 There are many types of medications used for pain, and often a combination of agents with differing mechanisms of action is most effective. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, produces analgesia, sedation, and amnesia.3,4 It has become both a popular and controversial analgesic for acute and chronic pain. Although ketamine is currently unavailable in an oral formulation, it is a versatile compound that can be administered via various routes including oral, parenteral, or inhalation. The following information is a review of literature on oral ketamine for pain published in the last 10 years.
A 2013 systematic review identified 5 randomized controlled trials and 6 prospective observational studies using ketamine for cancer pain in both children and adults.4 Three adult trials administered ketamine orally, and one case report of oral ketamine in children was included. The authors found an oral starting dose of 0.75 to 1.5 mg/kg/day to be typical amongst adult patients. Most studies were short-term, but one study continued therapy for up to 60 days. The authors considered oral ketamine to be a potential option for treatment-refractory cancer pain despite the limited data. Adverse events including somnolence, drowsiness, nausea/vomiting, and hallucinations were noted concerns with oral ketamine.
More recent literature for ketamine in chronic pain includes 2 randomized controlled trials and a retrospective, observational study.5-7 The retrospective study enrolled 51 patients with chronic, neuropathic pain.5 Most patients were initially treated with intravenous ketamine, then converted to oral ketamine; however, some patients initiated oral ketamine at a dose of 0.5 mg/kg/day in divided doses. Patients were titrated to appropriate pain control. Overall, ketamine was effective in 44% of patients, partially effective in 20%, opioid-sparing without pain reduction in 14%, and ineffective in 22%. The authors concluded that oral ketamine may be a useful alternative agent for pain. Fallon et al randomized 214 patients with cancer-related neuropathic pain to placebo or oral ketamine in addition to their pre-existing analgesic regimen.6 Initial doses of 40 mg/day were titrated to a maximum of 400 mg/day over a 2-week period followed by 16 days of stable dosing. At day 16, 22.4% of patients with ketamine had benefit compared with 25.2% of placebo patients. Thus, in this study, oral ketamine failed to reduce pain compared with placebo. In a smaller (N=42) randomized controlled trial, patients with neuropathic pain were randomized to oral methadone alone, oral ketamine alone, or methadone plus ketamine.7 Oral ketamine was dosed at 30 mg 3 times daily. All treatment groups had significant and similar reductions in pain compared to baseline with final visual analog scores of 1.3, 1.6, and 2.2 in the methadone, ketamine, and methadone/ketamine groups, respectively at 90 days.
Two randomized controlled trials evaluated oral ketamine for pain control in patients with burns.3,8 The doses used in these studies were much higher than those used for chronic pain; thus, the sedative and dissociative properties are expected to be more pronounced. Norambuena et al randomized 60 pediatric burn patients (age 1 to 5 years) to midazolam plus ketamine (5 mg/kg) or midazolam, acetaminophen, and codeine given 20 minutes prior to painful procedures.3 Using the Children’s Hospital Eastern Ontario Pain Scale (CHEOPS) score to evaluate pain, the authors found patients in the ketamine group to have better pain control with a score of 7.4 versus 8.9 (p=0.0245) in those treated with acetaminophen/codeine. A randomized, double blind, cross over study in 60 adults with thermal burns randomly assigned patients to ketamine (5 mg/kg) or dexmedetomidine given orally and crossed over to the other group the following day.8 The mean visual analog scale (VAS) scores were significantly better with ketamine than dexmedetomidine (67% decrease versus 44% decrease).
In a recent, smaller (N=23), randomized, double-blind, crossover study ketamine was evaluated as an inpatient rescue analgesic.9 Each participant received either sublingual ketamine (50 mg) or oral ketamine (50 mg). Oral ketamine had slower onset, but ultimately both routes had similar analgesic effects.
The American Society of Regional Anesthesia and Pain Medicine (ASRA) published consensus guidelines on intravenous ketamine for acute and chronic pain in 2018.10,11 These guidelines include brief recommendations for oral ketamine. For chronic pain, ASRA concluded that there was low-level evidence to support the use of oral ketamine at a dosage of 150 mg/day or 0.5 mg/kg every 6 hours.10 Recommendations for acute pain concluded that the evidence for oral ketamine in acute pain was limited, but evidence indicates it may provide short-term benefit. The evidence was also considered low level.11
With the absence of a commercially available oral ketamine dosage form, practitioners often question the preparation of an oral liquid dosage form. Most of the studies included in this review lack details regarding the preparation. However, Rigo et al reported combining 20 mL of a ketamine 50 mg/mL solution with 80 mL of normal saline for a final ketamine concentration of 10 mg/mL.7 Norambuena reported mixing the ketamine with orange syrup.3 Neither report had any additional details of the ketamine preparations.
McNulty and Hahn report a case of oral ketamine for use in a patient with chronic pain, anxiety, and depression in a palliative care setting.12 They describe preparation of a 40 mg/5 mL oral solution compounded from ketamine hydrochloride crystalline powder. The authors noted that due to the bitter taste of ketamine, flavors such as crème de menthe and chocolate-raspberry mask the taste of ketamine hydrochloride well. The beyond-use date of this preparation is 14 days when stored in a refrigerator.
Ketamine is a diverse pharmaceutical with a variety of reported uses administered via many different routes.13 Careful dosing consideration should be made based on the desired effect. The nonmedical or abuse potential of ketamine must also be considered prior to initiating therapy with oral ketamine. Due to its anesthetic and psychostimulatory properties, ketamine has been used recreationally, and toxicity concerns must be considered.
Overall, there is limited evidence to support oral ketamine for pain control in acute or chronic pain. For chronic pain, oral ketamine may be a potential option for treatment-refractory pain related to cancer or neuropathy; however, data are limited, and long-term outcomes are unknown. For acute pain, oral ketamine showed efficacy in pediatric and adult burn patients compared to other medications; however, the studies are small, and there is very little recent evidence in other acute pain situations.
- Zelaya CE, Dahlhamer JM, Lucas JW, Connor EM. Chronic pain and high-impact chronic pain among U.S. adults, 2019. Published November 2020. Accessed June 22, 2022. https://stacks.cdc.gov/view/cdc/97308#:~:text=Data%20from%20the%20National%20Health%20Interview%20Survey%20In,impact%20chronic%20pain%29%20in%20the%20past%203%20months.
- NIH analysis shows Americans are in pain. National Center for Complementary and Integrative Health. Updated August 11, 2015. Accessed June 8, 2022. NIH Analysis Shows Americans Are In Pain | NCCIH
- Norambuena C, Yañez J, Flores V, Puentes P, Carrasco P, Villena R. Oral ketamine and midazolam for pediatric burn patients: a prospective, randomized, double-blind study. J Pediatr Surg. 2013;48(3):629-34. doi: 10.1016/j.jpedsurg.2012.08.018.
- 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. doi: 10.1111/pme.12182.
- Marchetti F, Coutaux A, Bellanger A, Magneux C, Bourgeois P, Mion G. Efficacy and safety of oral ketamine for the relief of intractable chronic pain: A retrospective 5-year study of 51 patients. Eur J Pain. 2015;19(7):984-993. doi:10.1002/ejp.624
- Fallon MT, Wilcock A, Kelly CA, et al. Oral ketamine vs placebo in patients with cancer-related neuropathic pain: A randomized clinical trial. JAMA Oncol. 2018;4(6):870-872. doi: 10.1001/jamaoncol.2018.0131
- Rigo FK, Trevisan G, Godoy MC, et al. Management of neuropathic chronic pain with methadone combined with ketamine: A randomized, double blind, active-controlled clinical trial. Pain Physician. 2017;20(3):207-215.
- Kundra P, Velayudhan S, Krishnamachari S, Gupta SL. Oral ketamine and dexmedetomidine in adults’ burns wound dressing–A randomized double-blind cross over study. Burns. 2013;39(6):1150-6. doi: 10.1016/j.burns.2013.02.012
- Chong CC, Schug SA. Efficacy and tolerability of oral compared with sublingual ketamine lozenges as rescue analgesics in adults for acute pain: The OSKet Trial. Clin Drug Investig. 2021;41(9):817-823. doi:10.1007/s40261-021-01066-x
- Cohen SP, Bhatia A, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 ;43(5):521-546. doi: 10.1097/AAP.0000000000000808
- Schwenk ES, Viscusi ER, Buvanendran A, et al. Consensus guidelines on the use of intravenous ketamine infusions for acute pain management from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):456-466. doi: 10.1097/AAP.0000000000000806
- McNulty JP, Hahn K. Compounded oral ketamine for severe depression, anxiety, and pain in a hospice patient with end-stage chronic obstructive pulmonary disease, cardiopulmonary failure, and severe renal insufficiency: A case report. Int J Pharm Compd. 2012;16(5):364-368.
- Vadivelu N, Schermer E, Kodumudi V, Belani K, Urman RD, Kaye AD. Role of ketamine for analgesia in adults and children. J Anaesthesiol Clin Pharmacol. 2016;32(3):298-306. doi:10.4103/0970-9185.168149
Ngoc Vo, PharmD
PGY1 Pharmacy Practice Resident
Cook County Health
The information presented is current as of June 1, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.