Efficacy and Safety of Ketamine in the Treatment of Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Figures & data

Figure 1 Study selection PRISMA flow diagram.

Notes: Adapted from: Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Creative Commons.

Table 1 Study Characteristics According to Population and Setting

Author, Year	Country	Number of Randomized Participants	Mean Age Per Studied Group	Sex (Male, n)	Inclusion Criteria	Exclusion Criteria	Follow-Up (Weeks)
Eide, 1994^Citation38	Norway	8 (cross-over study)	I: 71.9 P: 71.9 (cross-over study)	I: 4 C: 4 (cross-over study)	Patients with post-herpetic neuralgia attending the Pain Clinic, The National Hospital, Oslo, Norway, that were able to and willing to participate.	Patients not to use analgesic medication the last 2 days before each test session.	3 weeks
Max, 1995^Citation39	USA	8 (cross-over study)	I:40 P:40 (cross-over study)	I: 0 C: 0 (cross-over study)	Patients with chronic posttraumatic pain and widespread mechanical allodynia that need to demonstrate symptoms and signs suggesting altered central nervous system processing of sensory input. All patients were required to have mechanical allodynia to light stroking with a cotton gauze pad extending at least 5cm from site of injury.	Not reported	3 days
Mercadante, 2000^Citation40	Italy	10 (cross-over study)	I: 57 C: 57 (cross-over study)	I: 7 C: 7 (cross-over study)	Patients with cancer and pain unrelieved by their dose of morphine and a Karnofsky status of 50 or more were selected for this study. No adjuvant drugs had been previously used.	Patients with coexisting liver or renal disease or with encephalopathy were excluded.	3 days
Lauretti, 2002^Citation41	Brazil	26	I: 46 ± 12 C: 47 ± 10	I: 6 C: 8	Patients aged between 21 and 65years, with neuropathic chronic pain for more then six months, refractory to NSAID, physiotherapy, antidepressants, tramadol or intravenous meperidine, were included.	Not reported	3 weeks
Kvarnstrom, 2003^Citation35	Denmark	12 (cross-over study)	I: 47 C: 47	I: 3 C: 3	Patients should be affected by peripheral nerve or root lesions of traumatic origin, with spontaneous and evoked pain in the cutaneous territory supplied by the injured nerve together with clinically demonstrable sensory deficit or sensory hyperfunction. The age of the patients should be between 20 and 75 years	Patients with drug abuse, cardiovascular disease or previous treatment with intravenous ketamine or lidocaine were not considered for the study.	1 week
Lynch, 2005^Citation36	Canada	92	Ketamine: 51 Amitriptyline: 51 Ketamine+Amitriptyline: 52 C: 52	Ketamine: 9 Amitriptyline: 11 Ketamine+Amitriptyline: 12 C: 15	Nonpregnant adult; Established diagnosis of postherpetic neuralgia, diabetic neuropathy, or postsurgical/post traumatic neuropathic pain; Moderate to severe pain all or most of the time persisting despite other treatment modalities; Pain has persisted for 3 months or longer; Presence of dynamic tactile allodynia or pinprick hyperalgesia in pain; Normal cognitive and communicative ability as judged by clinical assessment and ability to complete self-report questionnaires.	Evidence of another type of pain as severe as the pain understudy; Evidence of another type of neuropathic pain not included in this study; Major depression requiring treatment; Allergy to amitriptyline or ketamine; Ongoing use of a monoamine oxiDase inhibitor.	3 weeks
Vranken, 2005^Citation37	Netherlands	33	I (50 mg): 58.4 ± 12.3 I (75mg): 51.2 ± 14.3 C: 51.8 ± 11	I (50 mg): 5 I (75mg): 6 C: 5	Age 18 years or older; patients suffering from neuropathic pain caused by lesion or dysfunction in the central nervous system, and insufficiently responding to conventional medical therapy (including opioids, anticonvulsants, antidepressants, baclofen, a-adrenergic agonists, oral anesthetic antiarrhythmic agents). Neuropathic pain was described by at least one of the following: burning pain, paroxysmal episodes of shooting pain, or pain on light touch. Additionally, patients had to score above 12 on the Leeds Assessment of Neuropathic Symptoms and Signs questionnaire.	Patients were excluded from the study if they: were pregnant; had a history of intolerance, hypersensitivity, or known allergy to ketamine; had a known history of significant hepatic, renal, or psychiatric disorder; had a history of cardiac events including arrhythmias, congestive heart failure, or unstable angina; had poorly controlled hypertension (systolic BP above180 mmHg, or diastolic BP above 90 mmHg despite anti-hypertensive therapy); had a history of substance abuse.	1 week
Tonet, 2008^Citation42	Brazil	30	Not specified	Not specified	Adult patients with chronic neuropathic pain.	Not specified	4 weeks
Sigtermans 2009^Citation25	Netherlands	60	I: 43.7 ± 11.5 C: 47.5 ± 13.1	I: 8 C: 4	Patients who were diagnosed with Complex Regional Pain Syndrome Type-1, that was based on the International Association for the study of pain criteria.	Pain score of less than 5 of 10, age < 18 years, pregnancy/lactation, increased intracranial pressure, a history of psychosis, a serious medical disease (eg, cardiovascular, renal, or liver disease) and use of strong opioid medication.	12 weeks
Schwartzman 2009^Citation26	USA	19	I: 38 (mean) C: 45.5 (mean)	I: 0 C: 1	Patients diagnosed with CRPS based on the revised IASP (International Association for the Study of Pain) criteria; whose condition was intractable for a minimum of 6 months and had failed at least three therapies. The patients were ketamine naive and were of either gender including all racial or minority groups. The patient’s age was between 18 and 65 years.	Patients who were pregnant or had known substance abuse issues, glaucoma or thyrotoxicosis were excluded. Any subject that was unable to provide consent due to cognitive difficulties was not enrolled in this study. Patients with active litigation, compensation or disability issues related to their CRPS, and subjects on calcium channel or beta blockers due to the need to utilize clonidine with ketamine were excluded.	12 weeks
Amr, 2010^Citation28	Egypt	40	I: 48.6±10.1 C:48.7 ± 9.7	I: 16 C: 17	All patients had been exhibiting symptoms for over 6 months. The study’s inclusion process continued until the requested number of patients was reached.	Patients who had SCI at or above the C-4 level were excluded because of the risk of respiratory arrest. Other exclusion factors were: pre existing hypertension, angina, congestive cardiac failure, hepatic impairment, renal impairment, and an allergy to any drugs used in the study.	4 weeks
Amr, 2011^Citation27	Egypt	40	I: 48.6±10.1 C:48.7 ± 9.7	I: 16 C: 17	Duration of symptoms was more than six months in all patients. The process of inclusion into the study went on until the target number of patients was reached.	Patients with previous chronic anticoagulation therapy, coagulation disorders, infection in the back, bed sores, spine deformity, hepatic or renal impairment were excluded from the study.	8 weeks
Barros, 2012^Citation29	Brazil	12 (cross-over study)	I: 71.7 P: 71.7 (Cross-over study)	I:4 C:4	Post Herpetic Neuralgia patients seen at the Pain Management Clinic (HC-FMB-Unesp, Botucatu-SP), older than 18 years old and able to understand the Numerical Verbal Scale (NVS: 0 to 10) were invited to take part in the study.	Those presenting abnormal biochemical blood tests and skin lesions in the area of pain were not included in the study.	5 weeks
Niesters, 2013^Citation30	Netherlands	10 (cross-over study)	I: 54.4 ±4,2 C: 54.4 ±4,2 (cross-over study)	I: 2 C: 2 (cross-over study)	Patients were required to have at least two of the following symptoms in legs, arms, or both (in a stocking-glove distribution): (i) symmetrical dysesthesias or paresthesias; (ii) burning or painful feet with night-time worsening; or (iii) peripheral tactile allodynia. With respect to the QST, subjects were included if they had an abnormal warm and cold detection threshold, an abnormal warm and cold pain threshold, or allodynia.	Age18 or.80 yr; presence or history of a medical disease such as renal, cardiac, vascular (including hypertension), or infectious disease; presence or history of a neurological and psychiatric disease such as increased cranial pressure, epilepsy or psychosis; glaucoma; pregnancy; obesity (BMI.30); or use of strong opioid medication.	1 day
Kim, 2015^Citation31	South Korea	30	I: 69 C: 69	I: Not specified C: Not specified	Patients with reported pain resistant to conventional treatments, including stellate ganglion block, local anesthetic infiltration, epidural block, and systemic administration of anticonvulsants and antidepressants. Spontaneous pain with a visual analog scale (VAS) scoreN7 and lasting for≥6 months.	Patients were excluded if they had hypermagnesemia, hypercalcemia, abnormal electrocardiogram, asthma, any degree of heart block, or renal impairment (blood ureaN12 mmol/L and creatinineN150μmol/L) or were taking digoxin.	2 weeks
Rigo, 2017^Citation32	Brazil	42	Ketamine: 54 ± 12.4 Methadone: 52 ± 13.6 Keta+Metha: 45 ± 8.5	Ketamine: 6 Methadone: 6 Keta+Metha: 5	Patients who had experienced neuropathic pain for more than 6 months and who were poorly responsive to drugs used to treat neuropathic pain who were 22 to 77 years old from the Clinical Care & Pain Management. (HUSM)	Patients with a history of severe psychiatric disorder, misuse of illegal drugs, or hepatic disease were excluded.	12 weeks
Fallon, 2018^Citation33	UK	214	I: Not specified C: Not specified	I: Not specified C: Not specified	≥18 years old; histological cancer diagnosis; written informed consent; Index neuropathic pain related to underlying malignancy or resulting from treatment received for this; Index neuropathic pain (worst pain) ≥ 4 on 0–10 (VAS); McGill Sensory Scale Score > 5; Patient has had a trial of at least one adjuvant analgesic (gabapentin, pregabalin, amitriptyline) or has been offered these and declined; patient is able to comply with study procedures.	Patients who have received chemotherapy or radiotherapy in the preceding six weeks; who may have a change in tumoricidal treatment during the period of study; Diastolic pressure > 100 mmHg at screening; History seizures in last 2 years; currently taking class I-antiarrhythmic drugs; life expectancy less than two months; patient who are actively hallucinating; women of childbearing potential not using adequate contraception, patients with cerebrovascular disease; patients with psychotic disorders.	4 weeks
Pickering, 2019^Citation34	France	20 (cross-over study)	I: 55 ± 12 C: 55 ± 12 (cross-over study)	I:10 C: 10 (cross-over study)	Patients with at least 18 year of age, chronic pain for more than 3 months, peripheral or central pain requiring IV ketamine infusion, and no previous ketamine treatment (naïve patients).	Previous IV ketamine treatment; contraindication (1) to ketamine (hypersensitivity, uncontrolled high blood pressure, severe heart failure), (2) to magnesium (severe kidney failure), or (3) to sodium chloride (water inflation, fluid retention); medical/surgical history or drug treatment judged by the investigator to be incompatible with the trial; women of childbearing age without effective contraceptive method; pregnancy or lactation; involvement in another clinical trial; and inability to comply with protocol requirements.	35 days

Abbreviations: I, intervention group; C, control; NSAIDS, nonsteroidal anti-inflammatory drugs; CRPS, Complex Regional Pain Syndrome; IASP, International Association for the Study of Pain; SCI, spinal cord injury; QST, quantitative sensory testing; BMI, body mass index; VAS, visual analogic scale.

Table 2 Study Characteristics Related to Description of Intervention, Control, and Outcomes

Author, Year	No. of Randomized Patients in Intervention and Control	Description of Intervention	Dose	Description of Control	Measured Outcomes
Eide, 1994^Citation38	I:8 C:8 (cross-over study)	Ketamine (0,15 mg/kg), morphine (0.075 mg/kg) or saline (9 mg/mL NaCl) were given IV	Intravenous - Ketamine 0.15 mg/kg injected in 10 minutes or Morphine.	Saline solution	Assessment of allodynia, wind-up-like pain, tactile and thermal sensibility and pain, using VAS.
Max, 1995^Citation39	I:8 C:8 (cross-over study)	For 3 days, patients were given 2 hours of intravenous ketamine, alfentanil or placebo. If no pain relief after 60 minutes, the infusion rates were doubled at this time and again at 90 minutes.	Intravenous - Ketamine 0.75 mg/kg/h, can get doubled. Alfentanil 1.5 mcg/kg/min, can get doubled.	Saline solution – 0.375 mL/kg/h	Background pain and mechanical allodynia, each rated every 10 minutes on a VAS. At 10 minutes intervals, the side-effects were asked.
Mercadante, 2000^Citation40	I:10 C:10 (cross-over study)	On 3 separate days, patients received ketamine hydrochloride 0.25 mg/kg, 0.50 mg/kg, or saline solution as a slow intravenous bolus administered in 30 minutes.	Intravenous - Ketamine 0.25 mg/kg or 0.5 mg/kg, administered in 30 minutes.	Saline solution	Pain intensity; nausea and vomiting, drowsiness, confusion, and dry mouth; MMSE; arterial blood pressure and side effects.
Lauretti, 2002^Citation41	I: 10 (3 excluded) C:13	At intervention group was given 0.1 mg/kg ketamine (2 mL) in 1% lidocaine solution. At control Group was given 30 μg clonidine (2 mL) in 1% lidocaine solution. The epidural catheter was maintained for 3 consecutive weeks. The outcomes were assessed weekly.	Epidural catheter - 0.1 mg/kg racemic ketamine in 1% lidocaine solution, followed by 30 mg of 1% lidocaine. (Total dose – 0,3mg/kg/day)	30 μg preservative-free clonidine (2 mL) in 1% lidocaine solution followed by 30 mg of 1% lidocaine (3mL) (Total dose - 80 μg/day)	The pain intensity was assessed by a VAS in the days 1, 7, 14 and 21 by the beginning of the study.
Kvarnstrom, 2003^Citation35	I: 12 C:12 (cross-over study)	Effects of ketamine 0.4 mg/kg and lidocaine 2.5 mg/kg were investigated. All substances were given intravenously. Two intravenous cannulas were applied, one for the infusion and one for blood sampling.	Intravenous – Ketamine 0.4 mg/kg for 40 minutes	Saline solution	Sensibility to touch, static sensibility, thermal sensitivity and intensity of continuous spontaneous pain using a VAS. Measurements were taken at T:0 and then at T:15, T:45, T:60, T:120, T:150.
Lynch, 2005^Citation36	Ketamine 22 Amitriptyline 22 Ketamine + Amitriptyline 23 C:25	Treatments consisted of four topical creams, containing placebo (vehicle only), 2% amitriptyline,1% ketamine, or a combination of 2% amitriptyline and 1% ketamine.	Topical cream - 1% Ketamine, or 2% amitriptyline + 1% ketamine, 3 times/day for 3 weeks	Topical placebo (vehicle only)	Average daily pain intensity using an 11-point NRS McGill Pain Questionnaire, measures of allodynia and hyperalgesia, and patient satisfaction.
Vranken, 2005^Citation37	Ketamine 11 (50 mg)/11 (75mg) C:11	First, S(C)-ketamine50 mg will be compared with placebo. If S(C)-ketamine 50 mg turns out to be more effective than placebo, S(C)-ketamine 75 mg will be compared to S(C)-ketamine 50 mg.	Iontophoretic administration - Ketamine 50mg or 75mg for 5 days.	Isotonic saline solution – 3mL	Pain intensity measured by VAS, health status (Pain Disability Index and EQ-5D) and quality of life (SF-36).
Tonet, 2008^Citation42	I: 10 amitriptyline + carbamazepine + ketamine C: 13 amitriptyline + carbamazepine.	In the first group received amitriptyline (25 mg) + carbamazepine (600 mg) + ketamine (30 mg/day) patients in the second group amitriptyline (25 mg/day) + carbamazepine (600 mg/day). When there was a need for analgesic supplementation, codeine (30 mg) was administered.	Oral - Ketamine 30 mg/ day, for 4 weeks.	Amitriptyline 25 mg + carbamazepine 600mg	The patients were evaluated for pain intensity, weekly for four weeks, using the numerical pain scale.
Sigtermans 2009^Citation25	I: 30 C:30	Patients were given a 4.2-day intravenous infusion of low-dose ketamine or placebo using an individualized dosage based on effect (pain relief) and side effects (nausea/vomiting/psychomimetic effects).	Intravenous - Ketamine infusion rate started at 1.2 mcg/kg.min to a maximum of 7.2 mcg/kg.min	Normal saline solution	Spontaneous pain assessed by a NRS. Radboud Skills Questionnaire (RASQ) and the Walking Ability Questionnaire (WAQ); active range of motion, threshold for touch; skin temperature and volumetric measurements.
Schwartzman 2009^Citation26	I: 9 C: 10	Infusion of 100 mL of normal saline with or without ketamine for 4 h (25 mL/h) daily for 10 days (5 days on, 2 days off, 5 days on). First day, infusion was set to 50% of the maximum rate. Second day, the infusion was increased to 75% of the maximum rate. Third day, infusion was increased to the maximum rate and maintained.	Intravenous - Ketamine maximum dose - 0.35 mg/kg/h, not to exceed 25 mg/h.	Normal saline solution	Overall pain level, joint pain, pin hyperalgesia, touch allodynia, cold allodynia and deep pressure evoked pain, strength and facility of movement, McGill questionnaire, quality of life questionnaire and a pain questionnaire, sensory and motor tests were assessed.
Amr, 2010^Citation28	I: 20 C: 20 (cross-over study)	Intervention group received 80 mg ketamine over a 5-hour daily for 7 days and 300 mg of gabapentin 3 times daily. Control group received a saline infusion over 5 hours daily for 7 days and 300 mg of gabapentin 3 times daily.	Intravenous -Ketamine 80 mg administered in 5 hours, for 7 days	Isotonic saline 0.9%	VAS for pain was assessed prior to treatment, daily following the infusions for 7 days and one week after infusion termination. Side effects, were reported.
Amr, 2011^Citation27	I: 20 C: 20 (cross-over study)	Intervention group received 0.2 mg/Kg of ketamine (2 mL) through epidural injection. Control group received saline solution 0.9%(2 mL) through epidural injection. Both groups received gabapentin 300 mg 3 times/day.	Epidural infusion - 0.2 mg/Kg of preservative-free ketamine 2 mL.	Isotonic saline 0.9% 2mL	VAS for pain obtained pre-injection, 7, 15, 30, 45 and 60 days post injection. Patients were also asked to report any side-effects.
Barros, 2012^Citation29	I: 12 C: 12 (cross-over study)	Divided into two groups instructed to apply the ointment on the site of pain four times a day. After 15 days of treatment - washout period of seven days. After the washout period, treatments were inverted and carried out for the same time.	Topical Oinment - Ketamine 1%, during 15 days	Placebo ointment	Numerical Verbal Scale, Measured at the times: M1 – First 15 days of treatment; M2 start of washout; M3 – start of 15 days of crossover treatment; M4 – End of treatment.
Niesters, 2013^Citation30	I: 10 C: 10 (cross-over study)	Treatments were as follows: - 1h infusion of 0.57 mg/kg S(+) ketamine; - morphine bolus of 0.05 mg/kg followed by 0.015 mg/kg/h for 1 h; and a 1 h saline solution infusion.	Intravenous – Ketamine 0.57 mg/kg infusion duration of 1 hour	Isotonic saline 0.9% during 1 hour	Spontaneous pain scores were measured by NRS. Subjects were contacted after their treatment to determine the duration of pain relief. And conditioned pain modulation (CPM).
Kim, 2015^Citation31	I: 15 C: 15	Patients were randomly divided into 2 groups of 15 patients each, and ketamine 1 mg/kg or magnesium 30 mg/kg was administered intravenously for 1 hour after midazolam sedation.	Intravenous - Ketamine (1 mg/kg per hour) diluted in 0.9% normal saline to a final volume of 100 mL	Magnesium sulfate (30 mg/kg per hour) were diluted in 0.9% normal saline to a final volume of 100 mL	Pain was rated on a VAS during a 2-week follow-up. All patients also completed the Doleur Neuropathique 4 questionnaire at baseline and final visits.
Rigo, 2017^Citation32	I: 11 Methadone: 13 Methadone + Ketamine: 13	Patients were randomly allocated to receive one of the 3 treatments: 3 mg methadone, 30 mg ketamine, or 3 mg methadone plus 30 mg ketamine 3 times a day.	Oral – Ketamine 3mg during 3 months	Methadone 3mg or Methadone 3mg + Ketamine 30mg	During 90 days, we assessed pain scores using a 10-point VAS, allodynia, burning/shooting pain, and side effects
Fallon, 2018^Citation33	I: 107 C: 107	Randomized in two groups to receive ketamine or placebo across 2 weeks to an effective and tolerable dosage. The starting dosage was 40mg/d, with a maximum400 mg/d. Patients receive a stable dose for 16 days.	Oral – Ketamine 40–400 mg/d, during 2 weeks	Placebo	Duration of analgesic benefit using the Short Form McGill Pain Questionnaire. Mean and worst pain; Hospital Anxiety and Depression Score and serious adverse events.
Pickering, 2019^Citation34	I: 20 C: 20 (cross-over study)	Each patient received: placebo /placebo, ketamine /placebo, and ketamine /magnesium, every 35 days. After this, patients returned for the second randomization. They were re-evaluated and randomized if their pain intensity on the day of randomization was like pain intensity at inclusion. The same assessment was done before the third period.	Intravenous – Ketamine 0.5 mg/kg diluted in 45 mL saline solution	Magnesium 3000 mg administered over 30 min	Primary endpoint - area under the curve of daily pain intensity for a period of 35 days after infusion. Secondary endpoints - pain (at 7, 15, 21 and 28 days) and health-related, emotional, sleep, and quality of life questionnaires.

Abbreviations: I, intervention group; C, control; VAS, visual analogic scale; MMSE, Mini-Mental State Examination.

Table 3 Risk of Bias

Author, Year	Was the Randomization Sequence Adequately Generated?	Was Allocation Adequately Concealed?	Was There Blinding of Participants?	Was There Blinding of Caregivers?	Was There Blinding of Data Collectors?	Was There Blinding of Staticians?	Was There Blinding of Outcome Assessors?	Was Loss to Follow-Up (Missing Outcome Data) Infrequent?*	Are Reports of the Study Free of Suggestion of Selective Outcome Reporting?	Was The Study Apparently Free of Other Problems That Could Put It at a Risk of Bias?
Amr 2010^Citation28	Probably yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Probably yes	Definetely yes	Probably yes	Definetely yes	Definetely yes
Amr 2011^Citation27	Probably yes	Definetely yes	Definetely yes	Definetely yes	Probably yes	Probably yes	Probably yes	Probably yes	Definetely yes	Definetely yes
Barros 2012^Citation29	Probably yes	Probably yes	Definetely yes	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Definetely yes	Probably yes
Eide, 1994^Citation38	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Definetely yes	Probably yes
Fallon, 2018^Citation33	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Definetely not	Definetely yes	Definetely yes
Kim, 2015^Citation31	Probably yes	Probably yes	Definetely yes	Probably yes	Probably yes	Probably yes	Definetely yes	Definetely yes	Probably yes	Probably yes
Kvarnstrom, 2003^Citation35	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Probably yes
Lauretti, 2002^Citation41	Probably yes	Probably yes	Definetely yes	Probably yes	Probably yes	Probably yes	Probably yes	Definetely yes	Definetely yes	Probably yes
Lynch, 2005^Citation36	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely not	Probably yes	Probably yes
Max, 1995^Citation39	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Probably yes
Mercadante, 2000^Citation40	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Probably yes
Niesters, 2013^Citation30	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes
Pickering, 2019^Citation34	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes
Rigo, 2017^Citation32	Probably yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Probably not	Definetely yes	Definetely yes
Scwartzman, 2009^Citation26	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Probably yes	Probably not	Probably yes	Probably yes
Sigtermans, 2009^Citation25	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Probably yes
Vranken, 2005^Citation37	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes	Definetely yes

Figure 2 Risk of bias according to different domains.

Figure 3 Meta-analysis on the overall mean pain reduction. Forest plot is representing the comparison of the overall mean pain between group ketamine and ST.

Table 4 GRADE Evidence Profile for Clinical Outcomes

Quality Assessment						Summary of Findings					Certainty in Estimates
						Study Event Rates		Relative Risk or Average (CI 95%)	Anticipated Absolute Effects
No of Participants (studies) Follow-Up in Days	Risk of Bias	Inconsistency	Indirectness	Imprecision	Publication Bias	Control	Ketamine		Control^a	Ketamine
Pain Average at one week after treatment (p < 0.00001)
182 (5) 04–12 weeks	No serious limitations	Serious limitations^a	No serious limitations	Serious imprecision^b	Undetected					Average 2.14 pain reduction (2.65 less to 1.63 less) compared to control	XXOO LOW
Pain Average at two weeks after treatment (p = 0.0005)
152 (5) 02–12 weeks	No serious limitations	Serious limitations^a	No serious limitations	Serious imprecision^c	Undetected					Average 1.30 pain reduction (2.04 less to 0.57 less) compared to control	XXXO VERY LOW
Pain Average at four weeks after treatment (p < 0.00001)
122 (4) 04–12 weeks	No serious limitations	Serious limitations^a	No serious limitations	Serious imprecision^c	Undetected					Average 1.68 pain reduction (2.25 less to 1.12 less) compared to control	XXXO VERY LOW
Psychedelic effects (p=0.0007)
266 (9) 01–90 days	No serious limitations	No serious limitations	No serious limitations	Serious imprecision^c	Undetected	8/134	56/132	4.94 (2.76–8.84)	200 per 1000^d	788 more per 1000	XXOO LOW
Discomfort (p=0.03)
40 (2) 01–03 weeks	No serious limitations	No serious limitations	No serious limitations	Serious imprecision^c	Undetected	2/20	12/20	4.06 (1.18–13.95)	167 per 1000^e	511 more per 1000	XXOO LOW

Notes: Table Representing the Quality of the Evidence and Summary of Findings. ^aSerious limitations due to high heterogeneity (I²>60%). ^bSerious imprecision due to less than 400 patients/events. ^cSerious imprecision due to wide confidence intervals and less than 400 patients/events. ^dBased on data from Niesters, 2013. ^eBased on data from Kvarnstrom, 2003.

Figure 4 Meta-analysis on the average mean pain reduction. Forest plot is representing the comparison of the mean pain between group ketamine and ST according to time after the end of treatment.

Figure 5 Meta-analysis on the average mean pain reduction over time. Forest plot is representing the comparison of the mean pain in the ketamine at different time points compared to baseline pain.

Figure 6 Meta-analysis on the average standardized mean pain reduction. Forest plot is representing the comparison of the mean pain between group ketamine and ST according to different multidimensional pain scales.

Figure 7 Meta-analyses on the incidence of adverse outcomes. Forest plot is representing the comparison between group ketamine and ST according to different adverse outcomes.

Figure 8 Publication bias. Funnel Plot representing the distribution of studies according to their results.

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