A rapid positive influence of S-ketamine on the anxiety of patients in palliative care: a retrospective pilot study

Abstract

This retrospective pilot study (n=8) investigated whether the purified enantiomer S-ketamine (17.5mg/70kg) has a positive impact during the treatment of pain for patients within palliative care, and found that it alleviated psychological distress, depression, and anxiety.

“Background: Patients in palliative care need rapid-acting pharmacological options for psychological distress. N-methyl-D-aspartate antagonist ketamine is known to have a fast onset of anti-depressant and anxiolytic action. Its S-enantiomer S-ketamine (or esketamine) is an analgesic used as a routine treatment for refractory pain as an intravenous infusion (0.25 mg/kg over 45 min). This study investigates whether S-ketamine pain therapy has a positive impact on psychological distress caused by anxiety and depression in palliative care.

Methods: Patient routine data from a palliative care unit of a tertiary care hospital were used in a retrospective analysis after positive ethics approval. Eight patients, who received analgesic S-ketamine treatment, were compared to a control group matched by gender and age. The main analysis was conducted using three-way mixed MANOVA followed by two-way mixed ANOVA. Target variables were the values for anxiety and depression in the state-trait anxiety-depression inventory STADI. The predictor variables were the time of measurement before (T1) and after (T2) S-ketamine application and group membership.

Results: Comparison of the S-ketamine group (n = 8; 4 male, 4 female; average age 52 years) with the control group (n = 8; 3 male, 5 female; average age 55 years) revealed a significant multivariate effect on anxiety and depression F(1, 14) = 4.78; p = 0.046; r = 0.50. The univariate comparisons showed a significant reduction of the anxiety scores from T1 to T2 in the S-ketamine group compared to the control group F(1, 14) = 10.14; p = 0.007; r = 0.65. With regard to depression, there was no significant reduction from T1 to T2 in the group comparison F(1, 14) = 1.60; p = 0.23; r = 0.32. No long-lasting effects on pain were found.

Conclusions: Our findings show that psychological distress of patients in palliative care may improve after a single administration of S-ketamine, which mainly alleviates anxiety in those patients. Limitations of this study arise from non-randomization, retrospective analysis and low sample size. Therefore, further prospective and ideally randomized studies are necessary.”

Authors: Eduard Falk, Daniel Schlieper, Patrick van Caster, Matthias J. Lutterbeck, Jacqueline Schwartz, Joachim Cordes, Ina Grau, Peter Kienbaum & Martin Neukirchen

Summary

Patients in palliative care need rapid-acting pharmacological options for psychological distress. S-ketamine has been shown to have a positive impact on psychological distress caused by anxiety and depression.

Background

The total pain concept is useful in palliative care, as pain may occur on a physical, psychological, social and spiritual level. Ketamine is a non-competitive NMDA-receptor antagonist that is effective in the treatment of refractory cancer pain.

Ketamine has dose dependent analgesic and anesthetic properties with sympathomimetic side effects, and is used in clinical practice as a racemic mixture in a 1:1 ratio of the R-andS-enantiomer of ketamine and as pure S-ketamine. It is abused as a recreational drug and can cause addiction.

Nasal application of S-ketamine in combination with an oral antidepressant reduces treatment-resistant depression. This effect is attributed to an induction of neuroplasticity, which reverses the negative effect of stress and depression on neural cells and synapses.

Ketamine may be a good treatment option for patients in palliative care suffering from anxiety and depression. Ketamine has a rapid effect on stress, anxiety and depression and may be of huge importance for the treatment of psychiatric conditions of patients in palliative care.

In our specialized palliative care unit, S-ketamine is regularly used as an analgesic treatment for therapy refractory pain. A retrospective pilot study investigated whether an analgesic therapy with S-ketamine has a positive impact on psychological distress caused by anxiety and depression of patients in palliative care compared to a control group.

Study design

This pilot study analyzed routine patient data over a one-year period to compare the effects of S-ketamine and control group treatment. S-ketamine was used for pain control in the S-ketamine group, but control group treatment was not.

Setting

The analyzed data were collected in a clinical routine during a standard inpatient treatment in a specialized palliative care unit in Germany.

Primary study outcome variables

The State Trait Anxiety Depression Inventory (STADI) is a validated questionnaire for evaluating depression and anxiety as states and as traits. The STADI allows the calculation of scores for anxiety and depression, and can be interpreted as psychological distress in the sense of negative affectivity.

Potential confounding variables of primary outcomes

Pain is part of the Palliative Symptom Burden Score, which is routinely used in the SPCU. The NRS is used to assess pain, and a positive association between depression and pain is considered to be a potential confounder.

The AEDL is a measurement tool based on the concept of nursing process management. It is used to evaluate 9 aspects of physical functioning, role functioning and social functioning.

Psycho-oncological treatment was provided to patients in the form of psychotherapy, art therapy and animal-assisted therapy. The total amount of therapy time was used to indicate the amount of psychological and psycho-oncological treatment.

Patients received specialized palliative care every day of their stay, but the amount of palliative care treatment is considered a confounding variable.

Medication intake was considered because it may exert an acute effect on mood.

Secondary study outcome variables

S-ketamine was considered to have a prolonged positive influence on pain, restlessness and anxiety, and the ordinal scaled item restlessness/anxiety was used to assess these effects.

Time of assessments

Because STADI was assessed several times a week, the time span between STADI measurements was up to 4 days. The scores from the first of the three daily evaluations were used for the main analyses using the variables pain and restlessness/anxiety of the PSBS.

Statistical analyses

Data were analyzed using IBM SPSS 25.0 for Macintosh. A propensity score was calculated using logistic regression with age and gender as predictor variables and group membership as the target variable. The main analyses were conducted using multivariate and univariate analyses of variance, with group membership, measurement points, and difference between STADI anxiety and depression values as predictors. Nominal scaled confounders were included separately as covariates in an analysis of covariance.

The use of S-ketamine as a psychoactive drug was investigated. The use of repeated measures of restlessness/anxiety and the use of within subject factor as predictors were used as measures for prolonged psychotomimetic side effects.

Sample description

Eight patients who received S-ketamine for refractory pain improved from a clinical point of view, i.e. their STADI global levels decreased by more than 10 points.

The S-ketamine group had higher STADI values and moderate pain at T1 and Z2, compared to the control group, which had mild pain at Z1 and Z2.

The S-ketamine group differs descriptively from the control group with regard to pain, AEDL, psycho-oncological treatment, days with antidepressants, palliative care treatment and medication at both measurement points.

Primary study outcome variables

The reliability of all STADI scales was good, and there was a significant interaction between group and time. The effect of S-ketamine on anxiety and depression was similar in all groups.

A significant group-by-time interaction was observed regarding anxiety, with a large effect size, whereas there was no significant interaction between group and time regarding depression.

Potential confounding variables of primary outcomes

The reliability of the AEDL and test-retest reliability for pain were high, and the influence of confounders was considered in two-way mixed multivariate analyses of covariance. The results show that there was a significant interaction of group and time for anxiety.

The intake of benzodiazepines, antidepressants and opioids was considered separately for confounding influences, and a three-way mixed MANOVA was conducted with anxiety and depression as target variables. There was a strong and significant relationship between the intake of medication on T1 and T2.

The results show that the intake of benzodiazepines at T1 was a confounding variable in the three-way mixed MANOVA, but that the intake of antidepressants did not affect the improvement of the S-ketamine group.

Three-way mixed ANOVAs were calculated for benzodiazepines and antidepressants. The effect of antidepressants on anxiety was significant with a large effect size, but the effect of antidepressants on depression was not significant.

Secondary study outcome variables

Test-retest reliability for restlessness/anxiety at T2 showed high correlation ( = 0.92; p 0.001; n = 15), and no evidence for a persistent psychotomimetic effect of S-ketamine was found.

The change in pain from Z1 to Z2 was not significantly different between the S-ketamine group and the control group.

The results were different in the S-ketamine and control groups according to the STADI values of anxiety and depression at T1. Even with an alternative matching strategy, a significant effect of S-ketamine on anxiety remained.

Discussion

This retrospective pilot study provides the first evidence that S-ketamine may be useful in treating anxiety in patients in palliative care. S-ketamine has been approved by the FDA for treatment-resistant depression, but not for the treatment of anxiety in patients with a life-limiting disease.

S-ketamine reduced global STADI values by a clinically relevant level in 5 out of 8 patients. It is estimated that 2 patients are needed to treat.

The influence of S-ketamine on depression showed medium effect sizes, and the effect on anxiety was similar. There were no indications of sustained pain reduction by S-ketamine until the next morning.

S-ketamine has a pronounced effect on anxiety and depression in patients in palliative care, with a more pronounced reduction in anxiety over the first four days. In addition, both patients experienced an improvement in pain perception with a maximum of four and eight days after ketamine administration.

In our study, S-ketamine had no effect on depression in the group comparisons. However, a post-hoc sample size calculation showed that 20 patients are needed to determine a significant effect on depression.

In this study, more patients in the S-ketamine group died on the ward than in the control group. However, a causal relationship to S-ketamine is not plausible, since 60% of inpatients in the SPCU die on the ward, and ketamine racemate leads to no serious adverse events.

The S-ketamine group had higher STADI T-values, moderate pain, and needed more care than the control group, which may have reduced the possibility of participating in psycho-oncological interventions.

Limitations

This study has limitations due to its retrospective design, which prevented randomization, and because the data is not optimal to measure the effect of S-ketamine. However, the obtained data showed a stronger reduction of psychological distress caused by anxiety and depression one day after S-ketamine administration than four days after S-ketamine administration.

To minimize statistical errors, we generated another control group that took psychological distress into account. Still, the effect of S-ketamine was essentially the same in both groups.

Despite the limitation of our study, the results provide the basis for prospective studies on the use of S-ketamine in palliative care. These studies should include qualitative data and double-blinded, randomized and placebo-controlled trials.

Conclusions

In this retrospective study, S-ketamine significantly improved psychological distress in patients. Its rapid onset and anxiolytic and possible anti-depressant effects may improve palliative care.