Shots for everyone? A place for the placebo in the ED

The placebo effect has been studied for all manner of conditions, often with mixed to disappointing results^[4],[5]. Much of this is because it’s methodologically difficult to study; for obvious ethical reasons, investigators are generally unwilling to provide a ‘no treatment’ arm required to evaluate the placebo response.

Predictably, it has a differential effect depending on which condition is being treated. A Cochrane review of 202 trials including 6041 patients found that it was essentially ineffective for most conditions, with the exception of pain and anxiety^[6]. Another meta-analysis of 130 trials found similar results^[7]. One of the more promising studies, a meta-analysis of 30,981 migraine patients found a particularly large response to placebos at a rate of 30%^[8]. This makes sense – it seems that although pain may be a very real manifestation of pathology, it is intuitively more psychological and therefore more likely to respond to placebo than say, pancreatic cancer or a small bowel obstruction.

Interestingly, the degree of pain seems to influence responses as well. A classic study randomized 107 wisdom tooth removal subjects to receive either intravenous placebo in plain view or no treatment and asked them to rate their pain over the course of an hour. Investigators found that patients with pain ratings more than 2.6/10 were more likely to respond to placebo, suggesting pain must be at least moderate in order for placebo to be effective^[9].

The type of placebo also makes a difference. The Cochrane review above and another meta-analysis found that sham procedures were more effective than sham medications^[10],[11]. An RCT of 270 adults with arm pain that compared oral placebo medication versus sham acupuncture found that subjects were more responsive to sham acupuncture than sham medication^[12]. Importantly, multiple meta-analyses on the response to migraine treatments have found greater effects if the placebo is administered through subcutaneous rather than oral routes^[13],[14]. Taken together, this data strongly suggests that sham procedures are more likely to have a placebo effect than sham medications, and that sham medications are more likely to be effective if given by injection.

Lastly, a patient’s own expectation of treatment effectiveness may play an important role. In one study, 200 dental surgery subjects were randomized to receive sham or traditional acupuncture and asked to rate their pain in response to treatment. When the two groups were compared, no difference was observed. However, subjects were then asked whether they believed they had received the sham or traditional treatment. When they were analyzed based on belief, it was found that subjects who were convinced they received traditional acupuncture were more likely to respond (report more reduction in pain) than those who believed they were in the sham group, regardless of group to which they were randomized^[15]. A separate study pooling data from four acupuncture studies found similar results^[16]. From these data, investigators described an ‘expectancy effect’ – the self-fulfilling prophecy that patients who believe their pain will improve after a given treatment will actually have an improvement in pain compared to those more skeptical.

Several studies have demonstrated that oral ibuprofen has the same analgesic efficacy as IM keterolac, running contrary to any extra placebo-driven analgesic effect given by IM dosing^[17],[18]. These findings may highlight the importance of ‘selling’ the treatment to your patient to harness the expectancy effect and ‘contextual healing’^[19] discussed above – something not addressed by these trials.

Does this seem ethical? You could argue that we are pulling the wool over our patient’s eyes in partaking in this sort of treatment approach. However, if the data shows that under particular circumstances, a particular method of administration of a medication does actually make someone feel better, then it may be justified. To clarify – I wouldn’t advocate for treating a patient with a therapy that has no efficacy at all with the sole hope of achieving a placebo effect. I would argue that when treating pain or anxiety, a particular route of administration of medication may be more effective based on a psychological rather than pharmacological phenomenon.

The placebo effect has generally been shown to be ineffective, with the exception of having a small effect on treating pain. Procedural and injection-based therapy seems to harness this phenomenon most effectively, giving some credibility to intramuscular NSAIDs for the patient with a headache. Lastly, the placebo effect may be more pronounced if we “sell” our therapy in an effort to increase the expectancy effect.