Pain, depression, and substance use disorders are frequently comorbid; in particular, risk for developing substance use disorder (SUD) or major depressive disorder (MDD) has been measured as a function of pain and the amount of perceived disruption or interference pain has on activities of daily living and social functioning.1 The recent implication of abnormal glutamate signaling in each of these three disorders has sparked interest in the use of ketamine treatment both individually and when comorbid.2–4 The role of ketamine in both inhibiting peripheral pain input at the level of the presynaptic spinal neurons and modulating glutamate activity at multiple sites in the brain provides many therapeutic targets for pain, MDD, and SUDs.
Ketamine for Comorbid Depression and Pain Disorder
Ketamine is increasingly being used for MDD, particularly treatment-resistant depression (TRD), which is usually described as failure of at least two US Food and Drug Administration (FDA)-indicated antidepressants within a given mood episode.5 One study concluded that pain, not chronic disease, increases the likelihood of depression recurrence.6 Moreover, unexplained painful physical symptoms (UPPS) are experienced by approximately two-thirds of patients with depression.7 Unfortunately, UPPS make an accurate diagnosis of depression more difficult, and the presence of UPPS predicts poor response to the treatment and chronicity of depression.7 Elucidating shared neurobiological mechanisms modulated by ketamine increases justification of its use in the population of patients with comorbid pain and depression.
Ketamine's Mechanism of Action and Biomarkers in Comorbid Depression and Pain Disorder
Functional imaging studies of patients with pain who respond to ketamine compared to those patients with depression who respond to ketamine show changes in common areas of the brain, including, but not exclusive to, the prefrontal cortex, anterior cingulate cortex, insula, somatosensory areas, and thalamus.2,3,8 The orbital frontal cortex (part of the prefrontal cortex), anterior cingulate cortex, and insula have been implicated in the descending inhibition of pain; this neural pathway is activated in patients with chronic neuropathy pain after subanesthetic ketamine treatment.3 Upregulation of the N-methyl-D-aspartate (NMDA) receptor at the dorsal horn in the spinal cord is thought to amplify pain signals in chronic pain patients through a process called central sensitization.3 Pain control from ketamine treatment may result from both increasing inhibitory controls in the brain as well as decreasing afferent pain sensitivity at the spinal cord,3 whereas ketamine's role as an antidepressant has primarily been studied in the cortex and limbic system.
Ketamine-induced inhibition of NMDA receptors at presynaptic spinal dorsal horn neurons is thought to decrease the release of glutamate and substance P, and thus thought to decrease central sensitization pain signaling.3 Conversely, ketamine modulation of NMDA and/or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the prefrontal cortex is thought to increase the intrasynaptic glutamate neurotransmission responsible for antidepressant response.2 Ongoing research is attempting to study the various receptors ketamine affects in pain and depression. In addition to NMDA and AMPA receptors, opioid, muscarinic, monoaminergic, and sigma receptors likely play roles in both pain and depression response.2,3 As would be expected, studies in mice lacking the mu-opioid receptor suggest a role of the mu-opioid receptor in ketamine's acute-pain analgesic effect.3
Other potential biomarkers for both depression and chronic pain include increased levels of pro-inflammatory cytokines. Ketamine inhibits expression of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor, among others.2,3
Clinical Studies Using Ketamine to Treat Depression and Pain
Studies about complex regional pain syndrome (CRPS) are currently the most robust examinations of ketamine for treatment of chronic pain, but few studies have looked specifically at comorbid pain and psychiatric disorders. A study of CRPS type 1 pain by Sigtermans et al.9 attempted to examine whether improvement of anxiety and depression correlated with improved pain scores. Intravenous (IV) S(+)-ketamine at doses of 22.2 ± 2 mg/hour per 70 kg of body weight administered over 4.2 days significantly improved pain scores over the following 12 weeks.9 Although statistical analysis showed no correlation between the Hospital Anxiety and Depression Scale (HADS) or mental health status (MHS) on the 36-item Short Form Health Survey (SF-36) and improvement in pain scores, the authors noted that initial HADS and SF-36 MHS scores were too small for clinical diagnosis of depression or anxiety.9 Of note, Sigtermans et al.9 used only S(+)-ketamine as opposed to racemic ketamine because of a perceived lower risk of psychotomimetic side effects, whereas recent data from animal models suggest that R(−)-ketamine may hold the antidepressant potential.2
Another study administered daily oral ketamine at a dose of 0.5 mg/kg to 14 hospice patients and demonstrated a 100% antidepressant and anxiolytic response rate by days 14 and 3, respectively, which lasted through the 28 days of treatment.10 Of those patients with pain, there was no change in pain scores, so the authors concluded that improvements in mood and anxiety were independent of the possible effects of ketamine on pain.10
In patients with fibromyalgia, there is a lifetime prevalence of 90% for depressive symptoms and 62% to 86% for MDD.11 Two studies demonstrated a 50% reduction in pain in a majority of patients with fibromyalgia who were administered IV subanesthetic ketamine.12,13 Although these studies showed a rapid pain reduction for patients with fibromyalgia, they are limited by the number of infusions (1 or 2) and duration (2–8 weeks).12,13
Longer-term IV ketamine treatments over the course of 4 to 14 days for CPRS type 1 maintain high effect size (based on a meta-analysis, first week after treatment was 1.22 [95% confidence interval 0.82–1.61, P < .001] and fourth week after treatment was 0.39 [95% confidence interval 0.03–0.75, P = .036]) among responders until 4 weeks after treatment.3 Similarly, IV ketamine treatment three times per week over a period of 14 days for treatment-refractory depression demonstrated a median time to relapse of 18 days among responders.14 Therefore, ketamine treatment for pain, depression, or both comorbidly likely requires maintenance dosing to maintain response. Further study will be necessary to establish standards for maintenance regimens. Therefore, ketamine treatment for pain, depression, or both comorbidly likely requires maintenance dosing to maintain response. Further study will be necessary to establish standards for maintenance regimens.
Use of Ketamine to Decrease or Discontinue Prescribed Opiates
Ketamine is often used in concert with opiates to treat cancer pain, other acute and chronic pain, and for analgesia postoperatively. A review of 37 perioperative studies showed that in 27 cases use of ketamine resulted in less pain, nausea, and vomiting, with reduced morphine consumption.15 In cancer pain, adjunctive ketamine can potentiate analgesic efficacy, thereby decreasing opiate use, tolerance, and side effects.16
Acute and long-term opiate therapy may result in opiate-induced hyperalgesia.17 Ketamine used concurrently as an analgesic may prevent the development of opiate-induced hyperalgesia. It may also be a useful adjunct when further increases in opiates may decrease respiratory drive or may be intolerable or contraindicated for other reasons.
Opiates can effectively treat pain, but this often comes with the caveat of tolerance, dependence, or addiction. Ketamine's actions that limit tolerance to opiates may also be useful in the pharmacological management of opiate withdrawal. A randomized, double-blind, placebo-controlled study observed 58 patients with opiate dependence undergoing precipitated opiate withdrawal under general anesthesia.18 The participants with opiate dependence who received subanesthetic doses of ketamine (0.5 mg/kg per hour) during the rapid opiate antagonist induction under general anesthesia were found to have significantly better control of withdrawal symptoms during and after anesthesia at 48 hours. Withdrawal symptoms were measured by the Wang Modified Scale during anesthesia. For up to 48 hours after anesthesia, the ketamine group required statistically less clonazepam and carbamazepine for withdrawal symptoms. Cortisol levels were also measured in the two groups, with the ketamine group having statistically lower cortisol levels than the control group throughout precipitated withdrawal and 48 hours after.18
Ketamine As a Treatment for Substance Use Disorder
Ketamine shows promise in treating SUDs. Because ketamine is a glutamate modulator, it may help repair disruptions in glutamate neurotransmission that are implicated in the development of SUDs.4 Similar to pain disorders, chronic SUD appears to cause upregulation of NMDA receptors.19 Studies have examined ketamine's ability to exert unique post-glutamatergic effects on neuroplasticity and connectivity.20 Disruption by ketamine's inhibition of addiction feedback loops may increase motivation to change and decrease substance craving.
Dakwar et al.21 treated research volunteers who were cocaine dependent with a single subanesthetic infusion of ketamine at a dose lower than the standard antidepressant dose (0.41 mg/kg over 50 minutes) and found patients experienced increased motivation to abstain from drug use, as well as reduced cravings, relative to the active control drug (lorazepam). A subsequent ketamine infusion (0.71 mg/kg over 50 minutes) led to further reductions in craving. Nearly one-half of the participants maintained abstinence after completion of this inpatient study during the 4-week follow-up period, as confirmed by urine toxicology, despite not being interested in treatment at study entry. Infusions were well tolerated, with no adverse events or persistent psychoactive effects reported during follow-up.21
Ketamine-Assisted Psychotherapy for Substance Use Disorders
Ketamine was first used for SUD treatment via a psychedelic psychotherapy framework.22 Hoping to capitalize upon the psychedelic or psychoactive effects of ketamine, ketamine-assisted psychotherapy has been used to treat patients with alcohol, heroin, and cocaine dependence. In one study, patients treated with existential-type psychotherapy and higher subanesthetic doses of ketamine remained abstinent, had fewer cravings, and adopted a different outlook on life.22 Leveraging ketamine's psychoactive effects in the therapeutic setting may help patients develop important insights that lead to abstinent behaviors.22
In the study by Dakwar et al.21 that was mentioned previously, reanalyzed data from patients with cocaine dependence who received ketamine or lorazepam showed that mystical-type experiences (as rated by the Hoods mysticism scale) were higher when ketamine was administered at 0.71 mg/kg than when administered at 0.41 mg/kg, and were limited when 2 mg of lorazepam was administered. The authors found that the significant experiences of mystical-type events led to greater motivation to quit cocaine 24 hours after infusion.23
Krupitsky et al.24 have focused on harnessing the psychoactive effects of ketamine psychotherapeutically to facilitate a reappraisal of values with patients addicted to heroin. Other aspects of the psychotherapy used in this framework attempted to assist patients with SUD with cultivating a new set of priorities and ideals more consistent with sobriety. The beneficial effects of ketamine on positive treatment outcome seemed to be dose-dependent, with the high dose (2 mg/kg) of ketamine leading to significantly greater abstinence rates 2 years after administration than the lower dose (0.2 mg/kg).24
The subject of ketamine-assisted psychotherapy for patients with SUD is an area of interest to many investigators, and ongoing research is in progress.
The use of ketamine to treat comorbid pain, depression, and SUDs is a relatively recent development. As evidence for its efficacy in all three disorders continues to accumulate, physicians are coming to recognize uses for it outside of the emergency department and operating room. Given that ketamine can be obtained illicitly, physicians must exercise extreme caution with its therapeutic use in populations with pain and addiction. Understanding the current body of literature and the limitations will be crucial for its growth in these treatment-refractory comorbid populations.
- Barry DT, Pilver CE, Hoff RA, Potenza MN. Pain interference and incident mood, anxiety, and substance-use disorders: findings from a representative sample of men and women in the general population. J Psychiatr Res. 2013;47(11):1658–1664. doi:. doi:10.1016/j.jpsychires.2013.08.004 [CrossRef]
- Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signaling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16(7):472–486. doi:. doi:10.1038/nrd.2017.16 [CrossRef]
- Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77(2):357–367. doi:. doi:10.1111/bcp.12094 [CrossRef]
- Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuro-imaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002;159(10):1642–1652. doi:. doi:10.1176/appi.ajp.159.10.1642 [CrossRef]
- Wijeratne C, Sachdev P. Treatment-resistant depression: critique of current approaches. Aust N Z J Psychiatry. 2008;42(9):751–762. doi:. doi:10.1080/00048670802277206 [CrossRef]
- Gerrits MM, van Oppen P, Leone SS, et al. Pain, not chronic disease, is associated with the recurrence of depressive and anxiety disorders. BMC Psychiatry. 2014;14:187. doi:. doi:10.1186/1471-244X-14-187 [CrossRef]
- Jaracz J, Gattner K, Jaracz K, et al. Unexplained painful physical symptoms in patients with major depressive disorder: prevalence, pathophysiology and management. CNS Drugs. 2016;30:293–304. doi:. doi:10.1007/s40263-016-0328-5 [CrossRef]
- Sprenger T, Valet M, Woltmann R, et al. Imagng pain modulation by subanesthetic S-(+)-ktamine. Anesth Analg. 2006;103(3):729–737. doi:. doi:10.1213/01.ane.0000231635.14872.40 [CrossRef]
- Sigtermans MJ, van Hilten JJ, Bauer MC, et al. Ketamine produces effective and long-term pain relief in patients with complex regional pain syndrome type 1. Pain. 2009;145(3):304–311. doi:. doi:10.1016/j.pain.2009.06.023 [CrossRef]
- Irwin SA, Iglewicz A, Nelesen RA, et al. Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care: a 28-day open-label proof-of-concept trial. J Palliat Med. 2013;16(8):958–965. doi:. doi:10.1089/jpm.2012.0617 [CrossRef]
- Gracely RH, Ceko C, Bushnell MC. Fibromyalgia and depression. Pain Res Treat. 2012;2012:486590. doi:10.1155/2012/486590 [CrossRef].
- Noppers I, Niesters M, Swartjes M, et al. Absence of long-term analgesic effect from a short-term S-ketamine infusion on fibromyalgia pain: a randomized, prospective, double blind, active placebo-controlled trial. Eur J Pain. 2011;15(9):942–949. doi:. doi:10.1016/j.ejpain.2011.03.008 [CrossRef]
- Graven-Nielsen T, Aspegren Kendall S, Henriksson KG, et al. Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain. 2000;85(3):483–491. doi:10.1016/S0304-3959(99)00308-5 [CrossRef]
- Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250–256. doi:. doi:10.1016/j.biopsych.2012.06.022 [CrossRef]
- Bell RF, Dahl JB, Moore RA, et al. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006;(1)CD004603. doi:10.1002/14651858.CD004603.pub2 [CrossRef].
- Bell RF, Eccleston C, Kalso E. Ketamine as adjuvant to opioids for cancer pain. A qualitative systematic review. J Pain Symptom Manage. 2003;26:867–875. doi:10.1016/S0885-3924(03)00311-7 [CrossRef]
- van Dorp E, Kest B, Kowalczyk WJ, et al. Morphine-6beta-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans. Anesthesiology. 2009;110:1356–1363. doi:. doi:10.1097/ALN.0b013e3181a105de [CrossRef]
- Jovaisa T, Laurinenas G, Vosylius S, et al. Effects of ketamine on precipitated opiate withdrawal. Medicina (Kaunas). 2006;42(8):625–634.
- Uys JD, LaLumiere RT. Glutamate: the new frontier in pharmacotherapy for cocaine addiction. CNS Neurol Disord Drug Targets.2008;7(5):482–491. doi:10.2174/187152708786927868 [CrossRef]
- Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959–964. doi:. doi:10.1126/science.1190287 [CrossRef]
- Dakwar E, Levin F, Foltin RW, Nunes EV, Hart CL. The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers. Biol Psychiatry. 2014;76(1):40–46. doi:. doi:10.1016/j.biopsych.2013.08.009 [CrossRef]
- Krupitsky EM, Grinenko AY. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. J Psychoactive Drugs. 1997;29(2):165–183. doi:10.1080/02791072.1997.10400185 [CrossRef]
- Dakwar E, Anerella C, Hart CL, Levin FR, Mathew SJ, Nunes EV. Therapeutic infusions of ketamine: do the psychoactive effects matter?Drug Alcohol Depend. 2014;136:153–157. doi:. doi:10.1016/j.drugalcdep.2013.12.019 [CrossRef]
- Krupitsky E, Burakov A, Romanova T, Dunaevsky I, Strassman R, Grinenko A. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. J Subst Abuse Treat. 2002;23(4):273–283. doi:10.1016/S0740-5472(02)00275-1 [CrossRef]