Ketamine and fMRI for Neuropathic Pain

• ClinicalTrials.gov Identifier: NCT02373449
• Recruitment Status: Completed
• First Posted: February 27, 2015
• Last Update Posted: April 28, 2021
• Sponsor: University Health Network, Toronto
• Information provided by (Responsible Party): Anuj Bhatia, University Health Network, Toronto

Study Description

Brief Summary:

Neuropathic or nerve injury related pain (NP), an extremely unpleasant condition that is difficult to treat, often has a severe, persistent, and unremitting course. Conventional treatments are often ineffective in relieving NP. Recently, the investigators have developed a cost-efficient regimen involving use of low dose infusions of ketamine for treating neuropathic pain in patients in whom oral medications have failed. We have observed excellent benefits in many of these patients. However, this treatment requires titration and monitoring during the infusion and currently it is not possible to predict which patients will benefit from this intervention. The investigators have shown that functional magnetic resonance imaging (fMRI) of the brain can be used as a tool to predict relief of pain and to assess the effect of treatment in some chronic pain conditions. This innovative project involves development of an fMRI-guided treatment with intravenous ketamine in patients with NP. This study aims to analyze patterns of changes in fMRI of the brain, before and after infusion of ketamine and to correlate the changes with pain intensity. The information from this study will help to deliver this therapy earlier to those patients who are most likely to benefit from ketamine.

Condition or disease	Intervention/treatment	Phase
Neuralgia	Other: RS-fMRI; Drug: Ketamine	Not Applicable

Detailed Description:

This trial is exploratory, prospective, non-randomized, single cohort, single-center, with no blinding of participants, treating physicians, and investigators. Study participants undergo a resting-state fMRI before, after and at '1-month post-ketamine infusion' (standard care). Patients will be recruited over 2 years, from Pain Clinics at Toronto Western Hospital and Mount Sinai Hospital. The primary null hypothesis for this trial is that there are no fMRI brain patterns of patients with neuropathic pain that predict pain relief following ketamine infusion. The secondary null hypothesis for this trial is that there are no correlations between specific fMRI brain patterns of patients with neuropathic pain and change in intensity of pain immediately following ketamine infusion. Further secondary hypothesis include that cortical reorganization in the brain as measured by fMRI at one month after the infusion of ketamine does not correlate with persisting analgesic benefit in patients with neuropathic pain. Finally, we hypothesize that ketamine infusions do not provide significant pain relief, reduction in anxiety and depression, and improvement in quality of life early (at 1 month) and late (at 3 months) after the infusions in patients with neuropathic pain.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Functional Magnetic Resonance Imaging to Predict and Correlate Clinical Outcomes of Ketamine Infusions for Refractory Neuropathic Pain
• Study Start Date: February 2015
• Actual Primary Completion Date: December 2019
• Actual Study Completion Date: December 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: RS-fMRI; All subjects will be instructed to keep their eyes closed but to remain awake during the fMRI measurement. Resting State fMRI (RS-fMRI) will be performed within four weeks of planned infusion of ketamine, immediately after the end of infusion of ketamine on the fifth (last) day of infusion, and on the one month follow-up appointment after the infusion.	Other: RS-fMRI; Resting State-functional Magnetic Resonance Imaging. Protocols involving BOLD (blood oxygen level-dependent) and non-BOLD techniques will be used.; Drug: Ketamine; Part of standard care. To be performed over five consecutive days (Monday to Friday) for six hours per day. A therapeutic range of 0.5 to 2.0 mg/kg/hour is targeted.

Outcome Measures

Primary Outcome Measures :

1. Correlation between 'baseline (pre-infusion) fMRI patterns' and 'pain relief (>50% pain reduction, as per NRS or 'Numerical Rating Scale')' [ Time Frame: 1 month following ketamine infusion ]

Secondary Outcome Measures :

1. Correlation between 'specific fMRI brain patterns at 1-month post-infusion' and 'change in neuropathic pain intensity (as per NRS) at 3-month post-infusion' [ Time Frame: 3 months following ketamine infusion ]
2. Change in pain intensity at 1 month post-infusion, as measured by Brief Pain Inventory (BPI) [ Time Frame: 1 month following ketamine infusion ]
3. Change in pain intensity at 3 months post-infusion, as measured by Brief Pain Inventory (BPI) [ Time Frame: 3 months following ketamine infusion ]
4. Change in anxiety at 1 month post-infusion, as measured by Hospital Anxiety and Depression Scale (HADS) [ Time Frame: 1 month following ketamine infusion ]
5. Change in anxiety at 3 months post-infusion, as measured by Hospital Anxiety and Depression Scale (HADS) [ Time Frame: 3 months following ketamine infusion ]
6. Change in depression at 1 month post-infusion, as measured by Hospital Anxiety and Depression Scale (HADS) [ Time Frame: 1 month following ketamine infusion ]
7. Change in depression at 3 months post-infusion, as measured by Hospital Anxiety and Depression Scale (HADS) [ Time Frame: 3 months following ketamine infusion ]
8. Change in quality of life at 1 month post-infusion, as measured by Short Form-36 (SF-36) v2 Health Survey [ Time Frame: 1 month following ketamine infusion ]
9. Change in quality of life at 3 months post-infusion, as measured by Short Form-36 (SF-36) v2 Health Survey [ Time Frame: 3 month following ketamine infusion ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Refractory neuropathic pain diagnosed by a >3 score on DN4 (Douleur Neuropathique 4) questionnaire
• Average daily pain intensity should be moderate or severe, as indicated by a >3 score on NRS (Numerical Rating Scale)
• Duration of neuropathic pain should be more than three months
• Participants should have tried at least three medications for neuropathic pain. Each of these medications should belong to a different pharmacological group: anticonvulsants (gabapentin, pregabalin), tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine), serotonin noradrenaline reuptake inhibitors (venlafaxine, duloxetine), tramadol, opioids, cannabinoids, methadone, topical lidocaine and capsaicin patches.

Exclusion Criteria:

• Ketamine or lidocaine intravenous infusion within the 6 months preceding enrollment into this trial
• Contraindications to ketamine (allergy, pregnancy, uncontrolled arterial hypertension, uncontrolled hyperthyroidism, severe ischemic heart disease or heart failure, severe liver or kidney disease, space occupying lesion in the brain or the spinal cord, uncontrolled epilepsy and glaucoma)
• Ongoing litigation issues related to the patient's pain that may affect reporting of pain and quality of life
• An unstable medical or psychiatric condition that makes it unsafe to use study medications
• Participants unable to comply with the study protocol (e.g. follow-up visits, filling forms for measuring anxiety, depression, and quality of life)
• Relative (claustrophobia) or absolute contraindications for MRI

Contacts and Locations

Locations

Canada, Ontario

Toronto Western Hospital

Toronto, Ontario, Canada, M5T2S8

Sponsors and Collaborators

University Health Network, Toronto

Investigators

• Principal Investigator: Anuj Bhatia; UHN

More Information

• Responsible Party: Anuj Bhatia, Staff Anesthesiologist, University Health Network, Toronto
• ClinicalTrials.gov Identifier: NCT02373449
• Other Study ID Numbers: 14-8706-AE
• First Posted: February 27, 2015
• Last Update Posted: April 28, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Anuj Bhatia, University Health Network, Toronto:

Ketamine; fMRI; refractory neuropathic pain

Additional relevant MeSH terms:

Neuralgia; Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Ketamine; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action