Theresa Lii, M.D., M.S.

All Publications

• Opioids Diminish the Placebo Antidepressant Response: A Post Hoc Analysis of a Randomized Controlled Ketamine Trial. medRxiv : the preprint server for health sciences Lii, T. R., Flohr, J. R., Okada, R. L., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., Heifets, B. D. 2024

  Abstract

  The endogenous opioid system is thought to play a role in the placebo antidepressant response. A recent trial comparing the rapid antidepressant effects of ketamine versus placebo in surgical patients, some of whom were on chronic opioid therapy, revealed a substantial placebo effect. This finding provided an opportunity to test the hypothesis that opioid agonist exposure interacts with placebo antidepressant responses.This post hoc analysis utilized data from a previously reported randomized, anesthesia-blinded, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery. Mixed-effects models were used to determine whether baseline opioid use influenced antidepressant responses to the trial interventions, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) over 1 to 14 days post-treatment.The analysis showed that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, baseline pain intensity, and ethnicity. Additionally, there was negligible correlation between postoperative pain intensity and depression severity.This analysis was unregistered and conducted on a small sample; the findings need to be confirmed by prospective controlled studies.Opioid use at baseline attenuated the placebo antidepressant response independently of pain in depressed patients who received the study treatment under general anesthesia for routine surgery. The antidepressant response was preserved in opioid users who received intravenous ketamine.

  View details for DOI 10.1101/2024.09.24.24314243

  View details for PubMedID 39399033

  View details for PubMedCentralID PMC11469457

• "Evidence-based" needs to be based on evidence - a response to Giddon's letter regarding Edwards et al., Is there an association between lateralization of chronic pain in the body and depression? The journal of pain Gilam, G., Darnall, B., Edwards, K. A., Lii, T., Mackey, S. C., Ziadni, M. S. 2024: 104617

  View details for DOI 10.1016/j.jpain.2024.104617

  View details for PubMedID 38945382

• Prevalence and characteristics of preoperative patients with depression. British journal of anaesthesia Hietamies, T. M., Smith, A. E., Lii, T. R., Muzzall, E., Flohr, J., Okada, R. L., Andriella, Z. G., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Heifets, B. D. 2024

  Abstract

  Within the perioperative period, depression-related diagnoses are associated with postoperative complications. We developed a perioperative depression screening programme to assess disease prevalence and feasibility for intervention.Adult patients in multiple surgical departments at a single academic centre were screened for depression via the electronic health record patient portal or preoperative anaesthesia clinic before surgery, using the Patient Health Questionnaire (PHQ)-2 and -8. We utilised a broad method, screening all patients, and a focused method, only screening patients with a history of depression. Logistic regression was used to identify characteristics associated with clinically significant depression (PHQ-8 ≥10). Symptomatic patients were administered a brief psychoeducational intervention and referred for mental health services.A total of 3735 patients were identified by the broad and focused screens, of whom 2940 (79%) returned PHQ-2 data and were included in analysis. The broad screen (N=1216) found 46 (4%) patients who reported symptoms of moderate or greater severity. The focused screen (N=1724) found 242 (14%) patients with symptoms of moderate or greater severity and over all higher rates of depression across the symptom severity scale. Using the total screened pool, logistic regression identified a history of depression as the strongest associated patient characteristic variable but this did not capture most cases. Finally, we found that 66% of patients who were contacted about mental health services accepted referrals or sought outside care.At least 4% of preoperative patients have clinically significant symptoms of depression, most of whom do not have a chart history of depression.

  View details for DOI 10.1016/j.bja.2024.04.017

  View details for PubMedID 38782617

• Clinical Outcomes and Biomarkers From a Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients Heifets, B., Lii, T., Smith, A., Flohr, J., Nyongesa, C., Cianfichi, L., Hack, L., Schatzberg, A. ELSEVIER SCIENCE INC. 2024: S47

  View details for Web of Science ID 001282811900110

• Opioid Use Diminishes Placebo Antidepressant Response Independently of Pain in a Ketamine Depression Trial: A Post Hoc Analysis Lii, T., Smith, A., Flohr, J., Okada, R., Nyongesa, C., Cianfichi, L., Hack, L., Schatzberg, A., Heifets, B. ELSEVIER SCIENCE INC. 2024: S184-S185

  View details for Web of Science ID 001282811900431

• Is there an association between lateralization of chronic pain in the body and depression? The journal of pain Edwards, K. A., Lii, T., Schouten, T. D., Kearney, K. M., Ziadni, M. S., Darnall, B. D., Mackey, S. C., Gilam, G. 2024

  Abstract

  Depression commonly co-occurs with chronic pain and can worsen pain outcomes. Recent theoretical work has hypothesized that pain localized to the left hemibody is a risk factor for worse depression due to overlap in underlying neural substrates. This hypothesis has not been tested a priori. Using a large sample of treatment-seeking adults with mixed-etiology chronic pain (N=1,185), our cross-sectional study tested whether patients with left-sided pain endorse worse depressive symptoms. We also examined differences in other pain-related functioning measures. We tested four comparisons based on painful body areas using the CHOIR bodymap: 1) only left-sided (OL) vs. any right-sided pain; 2) only right-sided (OR) vs. any left-sided pain; 3) OL vs. OR vs. bilateral pain; and 4) more left-sided vs. more right-sided vs. equal-sided pain. ANOVA models showed OL pain was not associated with worse depression (F=5.50, p=.019). Any left-sided pain was associated with worse depression, though the effect was small (F=8.58, p=.003, Cohens d=.29). Bilateral pain was associated with worse depression (F=8.05, p<.001, Cohens d=.24-.33). Regardless of pain location, more body areas endorsed was associated with greater depression. Although a more rigorous assessment of pain laterality is needed, our findings do not support the hypothesis that left lateralized pain is associated with worse depression. PERSPECTIVE: Pain lateralized to the left side of the body has been hypothesized as a risk factor for worse depression in chronic pain, despite never being tested in a large, real-world sample of patients with chronic pain. Findings showed that more widespread pain, not pain laterality, was associated with worse depression.

  View details for DOI 10.1016/j.jpain.2024.02.004

  View details for PubMedID 38341013

• Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nature mental health Lii, T. R., Smith, A. E., Flohr, J. R., Okada, R. L., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., Heifets, B. D. 2023; 1 (11): 876-886

  Abstract

  Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials. We present a single-center, parallel-arm, triple-masked, randomized, placebo-controlled trial assessing the antidepressant efficacy of intravenous ketamine masked by surgical anesthesia (ClinicalTrials.gov, NCT03861988). Forty adult patients with major depressive disorder who were scheduled for routine surgery were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during usual anesthesia. All participants, investigators, and direct patient care staff were masked to treatment allocation. The primary outcome was depression severity measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received. A mixed-effects model showed no evidence of effect of treatment assignment on the primary outcome (-5.82, 95% CI -13.3 to 1.64, p=0.13). 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions. In conclusion, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. Although this masking strategy is impractical for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias.

  View details for DOI 10.1038/s44220-023-00140-x

  View details for PubMedID 38188539

  View details for PubMedCentralID PMC10769130

• Ketamine for Complex Regional Pain Syndrome: A Narrative Review Highlighting Dosing Practices and Treatment Response. Anesthesiology clinics Lii, T. R., Singh, V. 2023; 41 (2): 357-369

  Abstract

  This is a narrative review of intravenous ketamine infusions for the treatment of complex regional pain syndrome (CRPS). It briefly covers the definition of CRPS, its epidemiology, and other treatments before introducing ketamine as the article's focus. A summary of ketamine's evidence base and its mechanisms of action is provided. The authors then review ketamine dosages reported in peer-reviewed literature for the treatment of CRPS, and their associated duration of pain relief. The observed response rates to ketamine and predictors of treatment response are also discussed.

  View details for DOI 10.1016/j.anclin.2023.03.005

  View details for PubMedID 37245947

• Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients. medRxiv : the preprint server for health sciences Lii, T. R., Smith, A. E., Flohr, J. R., Okada, R. L., Nyongesa, C. A., Cianfichi, L. J., Hack, L. M., Schatzberg, A. F., Heifets, B. D. 2023

  Abstract

  BACKGROUND: Ketamine may have antidepressant properties, but its acute psychoactive effects complicate successful masking in placebo-controlled trials.METHODS: In a triple-masked, randomized, placebo-controlled trial, 40 adult patients with major depressive disorder were randomized to a single infusion of ketamine (0.5 mg/kg) or placebo (saline) during anesthesia for routine surgery. The primary outcome was depression severity measured by the Montgomery-Asberg Depression Rating Scale (MADRS) at 1, 2, and 3 days post-infusion. The secondary outcome was the proportion of participants with clinical response (≥50% reduction in MADRS scores) at 1, 2, and 3 days post-infusion. After all follow-up visits, participants were asked to guess which intervention they received.RESULTS: Mean MADRS scores did not differ between groups at screening or pre-infusion baseline. The mixed-effects model showed no evidence of effect of group assignment on post-infusion MADRS scores at 1 to 3 days post-infusion (-5.82, 95% CI -13.3 to 1.64, p=0.13). Clinical response rates were similar between groups (60% versus 50% on day 1) and comparable to previous studies of ketamine in depressed populations. Secondary and exploratory outcomes found no evidence of benefit for ketamine. 36.8% of participants guessed their treatment assignment correctly; both groups allocated their guesses in similar proportions.CONCLUSION: A single dose of intravenous ketamine compared to placebo has no short-term effect on the severity of depression symptoms in adults with major depressive disorder. This trial successfully masked treatment allocation in moderate-to-severely depressed patients using surgical anesthesia. While it is impractical to use surgical anesthesia for most placebo-controlled trials, future studies of novel antidepressants with acute psychoactive effects should make efforts to fully mask treatment assignment in order to minimize subject-expectancy bias. ( ClinicalTrials.gov number, NCT03861988 ).

  View details for DOI 10.1101/2023.04.28.23289210

  View details for PubMedID 37205558

• A literature review of the impact of exclusion criteria on generalizability of clinical trial findings to patients with chronic pain PAIN REPORTS Salmasi, V., Lii, T. R., Humphreys, K., Reddy, V., Mackey, S. C. 2022; 7 (6): e1050

  Abstract

  The ability of clinical trials to inform the care of chronic pain may be limited if only an unrepresentative subset of patients are allowed to enroll. We summarize and report new insights on published studies that report on how trial exclusions affect the generalizability of their results. We conducted a PubMed search on the following terms: (("eligibility criteria" AND generalizability) OR ("exclusion criteria" AND generalizability) OR "exclusion criteria"[ti] OR "eligibility criteria"[ti]) AND pain. We only considered studies relevant if they analyzed data on (1) the prevalence and nature of exclusion criteria or (2) the impact of exclusion criteria on sample representativeness or study results. The 4 articles that were identified reported differences in patients who were included and excluded in different clinical trials: excluded patients were older, less likely to have a paid job, had more functional limitations at baseline, and used strong opioids more often. The clinical significance of these differences remains unclear. The pain medicine literature has very few published studies on the prevalence and impact of exclusion criteria, and the outcomes of excluded patients are rarely tracked. The frequent use of psychosocial exclusions is especially compromising to generalizability because chronic pain commonly co-occurs with psychiatric comorbidities. Inclusion of more representative patients in research samples can reduce recruitment barriers and broaden the generalizability of findings in patients with chronic pain. We also call for more studies that examine the use of exclusion criteria in chronic pain trials to better understand their implications.

  View details for DOI 10.1097/PR9.0000000000001050

  View details for Web of Science ID 000884105700002

  View details for PubMedID 36398200

  View details for PubMedCentralID PMC9663135

• Management of Postoperative Pain in Patients Following Spine Surgery: A Narrative Review. International journal of general medicine Prabhakar, N. K., Chadwick, A. L., Nwaneshiudu, C., Aggarwal, A., Salmasi, V., Lii, T. R., Hah, J. M. 2022; 15: 4535-4549

  Abstract

  Perioperative pain management is a unique challenge in patients undergoing spine surgery due to the increased incidence of both pre-existing chronic pain conditions and chronic postsurgical pain. Peri-operative planning and counseling in spine surgery should involve an interdisciplinary approach that includes consideration of patient-level risk factors, as well as pharmacologic and non-pharmacologic pain management techniques. Consideration of psychological factors and patient focused education as an adjunct to these measures is paramount in developing a personalized perioperative pain management plan. Understanding the currently available body of knowledge surrounding perioperative opioid management, management of opioid use disorder, regional/neuraxial anesthetic techniques, ketamine/lidocaine infusions, non-opioid oral analgesics, and behavioral interventions can be useful in developing a comprehensive, multi-modal treatment plan among patients undergoing spine surgery. Although many of these techniques have proved efficacious in the immediate postoperative period, long-term follow-up is needed to define the impact of such approaches on persistent pain and opioid use. Future techniques involving the use of precision medicine may help identify phenotypic and physiologic characteristics that can identify patients that are most at risk of developing persistent postoperative pain after spine surgery.

  View details for DOI 10.2147/IJGM.S292698

  View details for PubMedID 35528286

• Comparison of intravenous lidocaine versus epidural anesthesia for traumatic rib fracture pain: a retrospective cohort study. Regional anesthesia and pain medicine Lii, T. R., Aggarwal, A. K. 2020

  Abstract

  BACKGROUND: Effective analgesia is essential in managing traumatic rib fractures. Intravenous lidocaine (IVL) is effective in treating perioperative pain, acute pain in the emergency department, cancer pain in hospice, and outpatient chronic neuropathic pain. Our study examined the associations between IVL versus epidural analgesia (EA) and pain for the treatment of acute rib fracture in the inpatient setting.METHODS: We performed a retrospective study involving adults admitted to an academic level I trauma center from June 1, 2011 to June 1, 2016 with consults to the pain service for acute rib fracture pain. Eighty-nine patients were included in the final analysis (54 IVL and 35 EA patients). Both groups had usual access to opioid medications. The primary outcome was absolute change in numeric pain scores during 0-24 and 24-48hours after initiating IVL or EA, compared with baseline. Secondary outcomes include opioid consumption, incentive spirometry, supplemental oxygens, pneumonia, endotracheal intubation and length of hospital stay.RESULTS: Numeric pain scores differed at baseline (mean 5.6 for IVL vs 4.5 for EA, p=0.01), while age, injury severity, and number of fractured ribs were similar. IVL and EA were associated with similar reductions in numeric pain scores within 0-24 and 24-48hours (mean -2.9 for IVL vs -2.3 for EA during both periods, p=0.19and p=0.17 respectively) . There was greater non-neuraxial opioid consumption with IVL compared with EA (98.6 vs 22.3 mg morphine equivalents (MME) at 0-24hours, p=0.0005; 105.6 vs 18.9 MME at 24-48hours, p<0.0001). When epidural opioids were analyzed, the EA group was exposed to higher total MME at 0-24hours (655.2 vs 98.6 MME, p<0.0001) and 24-48hours (586 vs 105.6 MME, p=0.0001), suggesting an opioid sparing effect of IVL.CONCLUSION: Our results suggest that IVL is similar to EA in numeric pain score reduction, and that IVL may have an opioid sparing effect when taking neuraxial opioids into account. IVL may be an effective alternative to epidurals for the treatment of rib fracture pain. It should be considered for patients who have contraindications to epidurals or are unable to receive an epidural in a timely manner.

  View details for DOI 10.1136/rapm-2019-101120

  View details for PubMedID 32503863

• Electroencephalographic signatures of pain and analgesia in rats. Pain LeBlanc, B. W., Bowary, P. M., Chao, Y. C., Lii, T. R., Saab, C. Y. 2016; 157 (10): 2330–40

  Abstract

  Pain modulates rhythmic neuronal activity recorded by Electroencephalography (EEG) in humans. Our laboratory previously showed that rat models of acute and neuropathic pain manifest increased power in primary somatosensory cortex (S1) recorded by electrocorticography (ECoG). In this study, we hypothesized that pain increases EEG power and corticocortical coherence in different rat models of pain, whereas treatments with clinically effective analgesics reverse these changes. Our results show increased cortical power over S1 and prefrontal cortex (PFC) in awake, freely behaving rat models of acute, inflammatory and neuropathic pain. Coherence between PFC and S1 is increased at a late, but not early, time point during the development of neuropathic pain. Electroencephalography power is not affected by ibuprofen in the acute pain model. However, pregabalin and mexiletine reverse the changes in power and S1-PFC coherence in the inflammatory and neuropathic pain models. These data suggest that quantitative EEG might be a valuable predictor of pain and analgesia in rodents.

  View details for DOI 10.1097/j.pain.0000000000000652

  View details for PubMedID 27347647

• T-type calcium channel blocker Z944 restores cortical synchrony and thalamocortical connectivity in a rat model of neuropathic pain. Pain LeBlanc, B. W., Lii, T. R., Huang, J. J., Chao, Y. C., Bowary, P. M., Cross, B. S., Lee, M. S., Vera-Portocarrero, L. P., Saab, C. Y. 2016; 157 (1): 255–63

  Abstract

  Oscillations are fundamental to communication between neuronal ensembles. We previously reported that pain in awake rats enhances synchrony in primary somatosensory cortex (S1) and attenuates coherence between S1 and ventral posterolateral (VPL) thalamus. Here, we asked whether similar changes occur in anesthetized rats and whether pain modulates phase-amplitude coupling between VPL and S1. We also hypothesized that the suppression of burst firing in VPL using Z944, a novel T-type calcium channel blocker, restores S1 synchrony and thalamocortical connectivity. Local field potentials were recorded from S1 and VPL in anesthetized rats 7 days after sciatic chronic constriction injury (CCI). In rats with CCI, low-frequency (4-12 Hz) synchrony in S1 was enhanced, whereas VPL-S1 coherence and theta-gamma phase-amplitude coupling were attenuated. Moreover, Granger causality showed decreased informational flow from VPL to S1. Systemic or intrathalamic delivery of Z944 to rats with CCI normalized these changes. Systemic Z944 also reversed thermal hyperalgesia and conditioned place preference. These data suggest that pain-induced cortical synchrony and thalamocortical disconnectivity are directly related to burst firing in VPL.

  View details for DOI 10.1097/j.pain.0000000000000362

  View details for PubMedID 26683108

• Cortical theta is increased while thalamocortical coherence is decreased in rat models of acute and chronic pain. Pain Leblanc, B. W., Lii, T. R., Silverman, A. E., Alleyne, R. T., Saab, C. Y. 2014; 155 (4): 773–82

  Abstract

  Thalamocortical oscillations are critical for sensory perception. Although pain is known to disrupt synchrony in thalamocortical oscillations, evidence in the literature is controversial. Thalamocortical coherence has been reported to be increased in patients with neurogenic pain but decreased in a rat model of central pain. Moreover, theta (4 to 8 Hz) oscillations in primary somatosensory (S1) cortex are speculated to predict pain in humans. To date, the link between pain and network oscillations in animal models has been understudied. Thus, we tested the hypothesis that pain disrupts thalamocortical coherence and S1 theta power in two rat models of pain. We recorded electrocorticography (ECoG) waveforms over S1 and local field potentials (LFP) within ventral posterolateral thalamus in freely behaving rats under spontaneous (stimulus-independent) pain conditions. Rats received intradermal capsaicin injection (Cap) in the hindpaw, followed hours later by chronic constriction injury (CCI) of the sciatic nerve lasting several days. Our results show that pain decreases coherence between LFP and ECoG waveforms in the 2- to 30-Hz range, and increases ECoG power in the theta range. These changes are short-lasting after Cap and longer-lasting after CCI. These data might be particularly relevant to preclinical correlates of spontaneous pain-like behavior, with potential implications to clinical biomarkers of ongoing pain.

  View details for DOI 10.1016/j.pain.2014.01.013

  View details for PubMedID 24457192