An Approach to Evaluate the Effects of Concomitant Prescribing of Opioids and Benzodiazepines on Veteran Deaths and Suicides (2019) / Chapter Skim
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2 Specifying the Target Trial
2 Specifying the Target Trial
Pages 43-70
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From page 43... ...
Chapter 3 follows by setting forth procedures for the use of observational data to emulate the target trials described in this chapter. For clarity, the committee uses the term "target trial" to refer to the hypothetical randomized trial that would directly address the research question; "protocol" to include all components of the design (e.g., patient enrollment, treatment strategies, outcome)
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From page 44... ...
Opioids can be initiated in multiple ways, including (1) patients with chronic pain are given an initial opioid prescription with the intent of treating them with long-term opioid therapy; (2)
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From page 45... ...
THE TARGET TRIAL FRAMEWORK The committee chose to employ a "target trial" methodology; that is, it created a hypothetical randomized trial and described how it can be emulated (i.e., closely approximated) by an observational study to address the research question.
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From page 46... ...
. An important thing to note is that observational data can only be used to emulate pragmatic target trials, that is, trials that compare treatment strategies currently in use and under the usual conditions in which they are applied in the real world (e.g., no placebo control, no blinding, no intensive monitoring)
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From page 47... ...
The protocol of the target trial, like that of any other randomized trial, includes seven components: eligibility criteria, treatment strategies, treatment assignment, start and end of follow-up, outcomes, causal contrasts, and the statistical analysis plan (Hernán and Robins, 2016)
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From page 48... ...
Specifically, one target trial examines the initiation of treatment for patients with chronic pain already taking benzodiazepines, and the other one examines strategies for the tapering of opioids in patients with chronic pain who are currently being treated with both benzodiazepines and opioids. Researchers may want to propose alternative target trials or variations of the committee's proposed trials, for example, trials with different eligibility criteria or treatment strategies.
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From page 49... ...
Nonetheless, Table 2-2 reflects a range of considerations for researchers to consult for finalizing the target trials and corresponding observational study designs that are not limited to options that could be based on available VA data. It is likely that limited availability and quality of observational data will result in a modification of the initial target trial specifications.
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From page 50... ...
Treatment Pain treatment modalities to Possible opioid dosage strategies to strategies consider: consider: • Opioids • No change • Other pharmacologic • Complete discontinuation treatments: • Speed of tapering o NSAID • Switch to buprenorphine o Anticonvulsants Non-opioid pain treatments that could o Antidepressants be included as additional strategies (e.g., o Topical therapies using a factorial design) : o Medical marijuana • Other pharmacological • Non-pharmacologic treatments; same list as Initiation treatments: Trial o Behavioral therapies • Non-pharmacological treatments; (e.g., cognitive same list as initiation trial behavioral therapy)
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From page 51... ...
• Specific pain diagnoses • Pain severity • History of overdose or suicide attempt (Same for initiation and tapering trials)
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From page 52... ...
Figure 2-1 illustrates the two trials described in Table 2-3. TABLE 2-3 Proposed Specifications for Initiation and Tapering Target Trials Protocol Component Initiation Target Trial Tapering Target Trial Eligibility Chronic pain diagnosisa Long-term opioid therapy defined as criteria 3+ opioid fills ≥21 days apart in a No prescriptions for opioids or ≥84-day period for ≥84-day supply non-aspirin NSAIDS in the past (Larochelle et al., 2016)
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From page 53... ...
, and also having a chronic pain diagnosis. End of follow-up: the earliest of 18 months,g death, or administrative end of follow-up (end of the study)
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However, researchers should consider that there might be a large proportion of veterans prescribed opioids for whom there is not a chronic pain diagnosis (Edelman et al., 2013)
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FIGURE 2-1 Opioid treatment initiation and tapering target trial schematic. NOTE: NSAID = nonsteroidal anti-inflammatory drug.
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Treatment Initiation Target Trial For the treatment initiation trial, the committee defined the eligible patient population to be patients with a chronic pain diagnosis currently
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TREATMENT STRATEGIES Opioids and benzodiazepines have distinct indications for use. Longterm opioid therapy is primarily used to treat chronic pain.4 It is important to note that long-term opioid therapy always begins as an initial prescription, likely intended to cover 1 month or less (rather than an initial prescription for long-term therapy)
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From page 58... ...
In the next sections, the committee defines the general treatment strategies to be considered in the treatment initiation and tapering target trials. Treatment Initiation Target Trial The committee considered major categories of pharmacologic therapies that are used for pain, which would include anticonvulsants, muscle relaxants, antidepressants, medical cannabis, and topical therapies.
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From page 59... ...
In the more specific clinical context sought to be addressed by this study, namely a patient with a chronic pain diagnosis not having used an opioid during the past 90 days while receiving chronic treatment with a benzodiazepine, a clinician could begin long-term therapy with an opioid, an NSAID, or both. The committee defined beginning opioid treatment (or NSAID treatment)
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From page 60... ...
. Opioid Dosage Measurement In the tapering target trial, patients would be eligible for inclusion into the study after their prescribed daily opioid dosage had reached a level that would be likely to induce opioid dependence.
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From page 61... ...
As in most pragmatic trials, the assignment would be non-blinded; that is, both patients and their treating physicians would be aware of the assigned treatment strategy. In the emulation of these target trials, treatment assignment is observed based on treatment records, requiring definitions of treatment groups that allow the creation of meaningful treatment groups and also allow for non-adherence to the assigned treatment that would occur in the target trial.
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OUTCOMES For the proposed research to be of value to clinicians and patients, it will be necessary for it to include outcomes that are relevant to treatment decisions. As mentioned previously, the committee chose all-cause mortality and death from suicide as the primary outcomes of interest for the proposed target trials.
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From page 63... ...
Clinicians concerned about exces sive restrictions on access to prescribed opioids have hypothesized that patients who have been on long-term opioid therapy are at an increased risk for suicide during and after opioid discontinu ation (Darnall et al., 2018; HP3, 2019)
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From page 64... ...
Two trials of the same treatment strategies conducted in the same population could have different intention-to-treat effects if their adherence patterns differed, and both would be internally valid effects of the assignment to treatment. The per-protocol effect is the effect of receiving the treatment strategies throughout the follow-up as specified in the study protocol (e.g., without non-adherence)
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From page 65... ...
That is true because intention-to-treat estimates are agnostic to post-randomization treatment decisions -- including discontinuation of the treatment strategies of interest, use of concomitant therapies, or any other deviations from protocol (Hernán and Hernández-Díaz, 2012)
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From page 66... ...
That is, per- protocol analyses of randomized trials can be viewed as observational analyses, which require the same methods and rely on the same assumptions as the analyses of observational datasets. The protocol of the target trial would therefore need to pre-specify the following three sets of adjustment variables: (1)
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From page 67... ...
Some of the variables used to explore this potential effect modification might also be included in the three sets of variables needed to adjust for confounding and selection bias. The sub-groups listed here will be explained in further detail in Chapter 3 in the discussion on why those same variables should be adjusted for confounding in the observational emulation of the target trials.
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From page 68... ...
2019. Association between opioid dose variability and opioid overdose among adults prescribed long-term opioid therapy.
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From page 69... ...
2017. VA/DOD clinical practice guideline for opioid therapy for chronic pain.
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