3Acute traumatic stress symptoms (first month): pharmacological interventions – adults

Q3. For adults with acute traumatic stress symptoms associated with significant impairment in daily functioning in the first month after a potentially traumatic event, do pharmacological interventions (benzodiazepines and antidepressants), when compared to treatment as usual, waiting list or no treatment, result in reduction of symptoms, improved functioning/quality of life, presence of disorder or adverse effects?

Background on the scoping question

Exposure to potentially traumatic events is common, and symptoms of acute stress in the aftermath of such events are frequently reported. A range of symptoms of acute stress exist, such as intrusion, avoidance, hyperarousal, hyperventilation, dissociation, insomnia and – in children – bedwetting. These symptoms are covered in different evidence profiles of these guidelines.

Acute traumatic stress symptoms in the current scoping question refers to symptoms of intrusion, avoidance and hyperarousal – when these are associated with significant impairment in daily functioning – in the first month after a potentially traumatic event. In terms of nosology, these symptoms can be part of:

  1. DSM-IV Acute Stress Disorder (not included in ICD), which in DSM is limited to one month of the event; and
  2. ICD-10 Posttraumatic Stress Disorder, which in ICD can be diagnosed within one month of the event.

Other symptoms of acute stress, including hyperventilation, conversion and dissociative symptoms, and secondary non-organic nocturnal enuresis in children, are the focus of other evidence profiles of these guidelines.

Pharmacological treatments, especially benzodiazepines, are commonly prescribed for people suffering symptoms of acute distress. However, there is currently no consensus on the effectiveness of pharmacological treatments between different clinical practice guidelines,11 making this an important scoping question.

PART 1. EVIDENCE REVIEW

Population/intervention/comparison/outcome (PICO)
  • Population: Adults with acute traumatic stress symptoms,12 within one month of exposure to a potentially traumatic event(s)
  • Interventions: Pharmacological interventions
  • Comparison: Placebo/active pharmacological treatment (benzodiazepines and antidepressants)
  • Outcomes:
    -

    Symptom severity post-intervention and at follow-up

    -

    Functioning/quality of life post-intervention and at follow-up

    -

    Presence of mental disorder post-intervention and at follow-up

    -

    Adverse effects (including tolerability).

Details of commissioned systematic review

NOTE: this systematic review was commissioned for a broader set of scoping questions, including pharmacological interventions for people with bereavement, PTSD and ASD. For this scoping question, the methodology of the review is presented for all studies, but only the results of studies relevant to adults with acute traumatic stress symptoms are discussed.

Types of studies

All double-blind, randomized, placebo controlled and comparative trials completed between October 2005 and October 2011 were considered in our primary and additional searches, covering 13 separate databases. Trials included in the NICE, Cochrane and ANCPTMH PTSD reviews were also considered.

Published and unpublished abstracts and reports were sought out in any language. Studies were not excluded on the basis of differences between them such as sample size or duration. Trials in which there was ongoing or newly initiated trauma-focused psychotherapy or where the experimental medication served as an augmentation agent to ongoing pharmacotherapy were excluded. Trials in which there was ongoing supportive psychotherapy were allowed, provided it was not initiated during the course of the treatment. Open label trials were not considered.

Types of participants

All studies were of subjects with PTSD, ASD or grief reactions. There was no restriction on the basis of different diagnostic criteria for PTSD, or duration or severity of PTSD symptoms. There was no restriction on the basis of co-morbid disorders, age or gender of participants.

Types of interventions

Pharmacological treatments for children and adults with PTSD, ASD or a grief reaction, in which the comparator was a placebo (active or non-active) or other medication.

Types of outcome measures

The primary outcomes of interest were clinician-administered PTSD symptom severity measures such as the Clinician Administered PTSD Scale (CAPS) and the Treatment Outcome PTSD Scale (TOP-8). Secondary outcomes of interest were remission rates, self-rated PTSD symptom scales such as the Impact of Event Scale (IES) and Davidson Trauma Scale (DTS) and measures of treatment response to co-morbid symptoms such as depression and anxiety (e.g. the Hamilton Depression Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory (BDI), the Hamilton Anxiety Scale (HAM-A) and the Covi Anxiety Scale (COV)). Measures of quality of life and functional disability such as the Sheehan Disability Scale (SDS) were also considered. The total number of participants who left the trial early due to any reason was used as a measure of treatment tolerability.

Search strategy

We conducted a primary bibliographic database search of MEDLINE, Medline In-Process, Embase, HMIC, PsycINFO, ASSIA and CINAHL using the Ovid interface. This initial broad search was intended to identify not only the randomized controlled trials (RCTs) of interest but other study methodologies and journal reviews of pharmacotherapy for PTSD.

The comprehensive search term used was created by amalgamating the previous search strategies from the NICE, Stein and Australian Guideline reviews with an updated list of medications.

Specific additional searches were carried out to identify international studies in Japanese, Chinese, Spanish and Portuguese (no additional studies identified). In addition, we searched the National PTSD Centre's PILOTS Database, the Cochrane Library, the Controlled Trials Register, Web Of Knowledge, OpenSIGLE and Google Scholar using the terms “post traumatic stress disorder” OR “PTSD” OR “posttraumatic stress disorder” OR “posttraumatic stress disorder” AND “treatment” OR “medication” OR “pharmacotherapy” AND “controlled”. Reference lists of all selected studies and reviews were further scrutinized for any additional RCTs.

Study selection

One reviewer transferred the initial search hits into EndNoteX4 software and duplicates were removed. Two reviewers then independently screened the titles and abstracts of RCTs identified from the search. Those that were clearly irrelevant were excluded and potentially relevant studies were then assessed for inclusion as full texts. Any discrepancies between reviewers' decisions were resolved by discussion and guidance from a third senior reviewer.

Data extraction and risk of bias assessment

One reviewer extracted the details of the studies into a standardized table which was then checked by another reviewer. Details from each study were collected on:

  • Study citation, year of publication, location, setting, number of centres, design, sample size, duration and length of follow-up, diagnostic criteria, inclusion and exclusion criteria;
  • Characteristics of study participants including gender distribution, mean and range of age, disease severity, duration of PTSD symptoms, presence of co-morbid depression, proportion with combat-related trauma, number randomized into each group, number of drop-outs;
  • Characteristics of interventions including mean and maximum doses;
  • Outcome measures reported including whether the data represented an intention-to-treat (ITT) or completers-only sample. For ITT samples, the method of imputation was noted.

One reviewer input outcome data into the Cochrane Collaboration's Review Manager 5 software, which was then checked by another reviewer. Data from studies included in previous systematic reviews were extracted by one reviewer and independently cross-checked by a second reviewer for accuracy. Risk of bias was independently assessed for each trial by two reviewers using the domain-based evaluation method recommended by the Cochrane Collaboration. This method considers the following domains: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete outcome data; selective reporting; and other sources of bias. Discrepancies between the two raters were resolved by discussion and arbitrated by a third senior rater. Masked study assessment (hiding details of publishing journal, author, etc.) was not undertaken, since it is unclear whether this reduces bias.

Data analysis

Review Manager 5 software was used to synthesise data using meta-analysis and to provide forest plots for dichotomous and continuous data. Confidence intervals (CI) of 95% were used for all analyses.

Categorical outcome measures such as leaving the study early were analysed using relative risk (RR) calculations. For continuous data, standardized mean differences (SMD) were used.

The degree of heterogeneity between studies was calculated using the I2 statistic. Where the statistic was less than 30%, indicating a mild degree of heterogeneity, a fixed effects model was used. A random effects model was used when the statistic was greater than 30%.

Data was analysed from the ITT sample in the “once randomized always analysed” fashion where possible to avoid effects of bias from completers-only analyses.

Results

No RCTs of pharmacotherapy for adults with acute traumatic stress were identified.

PICO table
Serial no.Intervention/comparisonOutcomesSystematic reviews used for GRADEExplanation
1Pharmacological interventions vs. placebo/active pharmacological treatmentSymptom severityNo data
FunctioningNo data
Presence of disorderNo data
Adverse effectsNo data

PART 2. FROM EVIDENCE TO RECOMMENDATION(S)

Evidence to recommendation table
BenefitsIn adults with acute traumatic stress within the first month after experiencing a potentially traumatic stressor, there is no evidence on the effect of benzodiazepines and antidepressants on symptom severity, functioning and presence of disorder.

A classic non-RCT study by Gelpin and colleagues (1996; Journal of Clinical Psychiatry) showed no benefits of benzodiazepines between 13 matched pairs of recent trauma survivors.
HarmsIn adults with acute traumatic stress, there is no evidence on the adverse effects of benzodiazepines and antidepressants.

For benzodiazepines, in addition to the evidence from randomized trials, data from observational and epidemiological studies highlighted a risk of tolerance and dependence. According to NICE UK, one of the key concerns about the use of benzodiazepines is that many people develop tolerance to their effects, gain little therapeutic benefit from chronic consumption, become dependent on them (10–30% of chronic benzodiazepines users are physically dependent on them) and suffer a withdrawal syndrome when they stop taking them (50% of all users suffer withdrawal symptoms).

The withdrawal syndrome includes anxiety, depression, nausea and perceptual changes.

There are also problems of abuse with benzodiazepines as they enhance and often prolong the “high” obtained from other drugs and alleviate their withdrawal effects.

The safety of psychotropic drugs in pregnancy and breastfeeding is not clearly established. In particular, exposure to benzodiazepines during the first trimester is associated with an increased risk of oral clefts, and exposure during the third trimester is associated with neonatal difficulties. For antidepressants, the risks of taking tricyclic antidepressants during pregnancy and when breastfeeding are better established than those of SSRIs and newer drugs. Antidepressants appeared not to be teratogenic, although SSRI exposure in late pregnancy may increase the risk of persistent pulmonary hypertension.
Value and preferences
In favourThe possibility of decreasing symptoms of acute traumatic stress and improving functioning/coping in stressful environments are important values.
AgainstProviding medication for acute traumatic stress may contribute to the medicalization of normal psychological reactions and contribute to dependence.
Feasibility (including economic consequences)Training is required in the understanding and safe administration of all psychotropic medications. To avoid the risks of harm referred to above, training of primary care practitioners may be necessary on responsible use of benzodiazepines.

In many LMIC settings, continuous availability of psychotropic drugs in non-specialized health care is a challenge.

Benzodiazepines are associated with low acquisition costs. Both generic tricyclic antidepressants and many generic selective serotonin re-uptake inhibitors are associated with low acquisition costs.

Diazepam (as a representative of the benzodiazepines) is included in the WHO list of essential medicines for the treatment of anxiety disorders. Amitriptyline (as a representative of the tricyclic antidepressants) and fluoxetine (not as a representative of SSRIs) are included in the WHO list of essential medicines for the treatment of depressive disorders.

Both diazepam and amitriptyline are included in the Interagency Emergency Health Kit (IEHK), a box with medicines and medical supplies designed to meet the expected primary health-care needs of people exposed to major humanitarian emergencies.
Judgements to inform the decision on the strength of the recommendation
FactorDecision
Is there high- or moderate-quality evidence?
The higher the quality of evidence, the more likely is a strong recommendation.
Yes
No X (benzodiazepines and antidepressants)
Is there certainty about the balance of benefits versus harms and burdens?
In the case of positive recommendations (a recommendation to do something), do the benefits outweigh harms?
In the case of negative recommendations (a recommendation not to do something), do the harms outweigh benefits?
Yes X (benzodiazepines)
No X (antidepressants)
Are the expected values and preferences clearly in favour of the recommendation?Yes X (benzodiazepines and antidepressants)
No
Is there certainty about the balance between benefits and resources being consumed?
In the case of positive recommendations (recommending to do something) is there certainty that the benefits are worth the costs of the resources being consumed?
In the case of negative recommendations (recommending not to do something) is there certainty that the costs of the resources being consumed outweigh any benefit gained?
Yes X (benzodiazepines and antidepressants)
No
Final recommendation by the guideline panel

Recommendation 3

Benzodiazepines and antidepressants should not be offered to adults to reduce acute traumatic stress symptoms associated with significant impairment in daily functioning in the first month after a potentially traumatic event.

For benzodiazepines:

Strength of recommendation: strong

Quality of evidence: very low

For antidepressants:

Strength of recommendation: standard

Quality of evidence: very low

Remarks

Clinicians should rule out concurrent disorders that may warrant treatment with benzodiazepines and antidepressants.

There is already a WHO (2010) mhGAP recommendation to offer access to psychological first aid to people who have been recently exposed to potentially traumatic events. In addition, recommendation 1 (on psychological interventions for acute traumatic stress symptoms in adults) is that “cognitive-behavioural therapy (CBT) with a trauma focus should be considered in adults with acute traumatic stress symptoms associated with significant impairment in daily functioning”. When combined, these recommendations imply that psychological first aid and (where resources exist) CBT should be considered in adults with acute traumatic stress symptoms associated with impairment in daily functioning in the first month after a potentially traumatic event.

11

Forbes, et al. A guide to guidelines for the treatment of PTSD and related conditions. Journal of Traumatic Stress. 2010;23(5):537–52. [PubMed: 20839310].

12

Acute traumatic stress symptoms in this scoping question refers to symptoms of intrusion, avoidance and hyperarousal associated with significant impairment in daily functioning in the first month after a potentially traumatic event.

From: Annex 5, Evidence Profiles

Cover of Guidelines for the Management of Conditions Specifically Related to Stress
Guidelines for the Management of Conditions Specifically Related to Stress.
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