VA/DoD CLINICAL PRACTICE GUIDELINE FOR OPIOID THERAPY FOR CHRONIC PAIN

VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain
Another RCT considered the safety and efficacy of oxycodone/naloxone prolonged-release relative to
oxycodone prolonged-release in 184 patients with moderate-to-severe chronic cancer pain at four-week
follow-up.[144] An observational study (not included in the evidence review) suggested that the
introduction of abuse deterrent opioid formulations did not help reduce abuse of opioids as a class and
that patients may switch from one opioid to another based on the availability or the lack of availability of
abuse deterrent formulations.[145]
Future research is needed to ascertain whether abuse deterrent formulations actually reduce OUD when
used for chronic pain, and whether said formulations differ across clinical outcomes such as pain, function,
and adverse events.
Dual-Mechanism Opioids
Dual-mechanism opioids include formulations of an opioid medication with a selective serotonin reuptake
inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Two common examples are
tramadol and tapentadol. While both are dual-mechanism opioids, they differ in their affinity for the mu
opioid receptor, resulting in partial vs. full agonist effects, and as such are discussed separately.
Tramadol
There is low quality evidence that tramadol may be more effective than placebo for pain relief. In one
short-term study, compared to placebo, tramadol was more effective for pain.[146] There is no long-term
evidence of the comparative efficacy of tramadol versus another opioid or a non-opioid comparison such
as non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen. Due to tramadol’s partial mu
agonist activity and demonstrated safety profile when used in conjunction with acetaminophen in elderly
patients, it may be a preferred agent in that patient group.[147,148]
Tapentadol
In long-term studies, compared to placebo, low quality evidence indicates that tapentadol is more
effective for pain-related primary and secondary outcomes, but results were mixed for several different
self-reported quality of life measures in these studies.[149-151] Compared to oxycodone, moderate
quality evidence suggests that tapentadol might be more effective for pain relief. Low quality evidence
suggests there is no difference in serious adverse events. Moderate quality evidence suggests tapentadol
might be superior for avoiding non-serious adverse events or discontinuation of treatment due to adverse
events; however, the clinical implications of these findings are unclear.[149]
Safety and Risk Mitigation
All recommendations in this CPG apply dual-mechanism opioid products, including the recommendations
regarding safety measures and risk mitigation strategies (e.g., to monitor for suicidality, accidental
overdose, and OUD).
Dual-mechanism opioid medications have additional considerations as a result of their dual action. They
include a lowering of seizure threshold in susceptible patients and the risk of serotonin syndrome.
Evidence related to safety of dual-mechanism opioids versus placebo was reviewed. No evidence on the
safety of tramadol met our inclusion criteria, and no new evidence was reviewed. Tramadol may be
considered lower-risk than tapentadol due to its mechanism of action and existing safety profile as noted
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