The American Academy of Pain Medicine’s 36th Annual Meeting was held February 26-March 1, 2020, in National Harbor, MD. The theme of the meeting was Innovation & Technology in Pain Medicine.

This year’s meeting clearly had a different tone than in years past. It emphasized multidisciplinary options to treating pain, rather than a primarily drug-based approach. Clinicians have advocated for decades for multidisciplinary care, so it was a welcomed theme.

However, medications—including opioid analgesics—remain an important part of the therapeutic arsenal. As the pendulum swings from liberal to conservative opioid prescribing, many patients in need are denied access to opioids and are burdened with untreated, or undertreated, pain. Alternative pain therapies such as acupuncture and yoga work for some patients. Still others may be able to find relief from over-the-counter medications.

However, other people in pain may need prescription medication. With the public pressure to prescribe fewer conventional opioids such as oxycodone, morphine, or hydrocodone, many physicians are seeking alternative drugs to treat pain without many of the problems associated with conventional opioids.

My colleague, Richard Rauck, M.D., Pain Fellowship Director at the Wake Forest University of Medicine, and I presented a Continuing Medical Education (CME) symposium at the meeting on atypical opioid options. We discussed the strengths and weakness of three atypical opioids—tramadol, tapentadol, and buprenorphine—that clinicians may consider for the appropriate patients.

Strengths and Weakness of Atypical Opioids

Our presentation began by noting that all opioids are not the same; most importantly, they vary in their safety profiles. They also differ in efficacy and must be tailored to the individual. However, when a patient needs medication to relieve pain and conventional opioids are unavailable (because a doctor is unable, or unwilling, to prescribe them), atypical opioids may be preferable to alternatives.

Atypical opioids may have a more favorable risk-benefit profile than conventional opioids, which have both analgesic and adverse effects. The larger therapeutic window between desired effects and unwanted consequences atypical opioids offer provides a greater margin of safety for most patients.

Each atypical opioid has unique characteristics. The strengths and weakness of each atypical opioid is discussed below.

Tramadol’s Benefits and Risks Are Variable

Tramadol is a schedule IV opioid. That means it carries “a low potential for abuse and low risk of dependence,” according to the United States Drug Enforcement Administration (DEA). However, tramadol gets its analgesic properties from O-desmethyltramadol (M1), which is a metabolite. That means, without M1, tramadol is unable to relieve pain. The creation of M1, in turn, is dependent upon an individual’s metabolism of tramadol which is under the control of the CYP2D6 gene. Unfortunately, there are common mutations of this gene that can cause tramadol to be metabolized at different rates. So how efficiently a patient metabolizes tramadol—and, therefore, how well tramadol works to relieve pain—depends on an individual’s genotype.

In addition, compared to conventional opioids, tramadol has been shown to possess a lower risk of causing respiratory depression. However, in combination with some drugs that raise serotonin levels, tramadol can increase the chances of inducing seizures and serotonin syndrome.

Tapentadol May Have Less Potential for Abuse

On the other hand, tapentadol is a schedule II opioid that is considered to pose a high risk of abuse and severe dependence. However, unlike tramadol, it does not require a metabolite for analgesia, and it does not increase serotonin levels. It also appears to have less risk of causing respiratory depression than conventional opioids.

Additionally, a systematic nine-year review showed single-drug overdoses involving tapentadol was very infrequent, which suggests tapentadol has a better safety profile than conventional opioids. The relative lack of overdoses or treatment for addiction in tapentadol users suggest tapentadol may have less abuse potential than other schedule II opioids.

Buprenorphine’s Advantages and Misconceptions

In contrast to tramadol and tapentadol, buprenorphine has multiple mechanisms of action. It limits the involvement of cellular activities that are thought to be responsible for most adverse effects in opioids. Also, because of its mechanisms of action, buprenorphine does not appear to develop tolerance. That’s a good thing, because tolerance would lead to a lack of effectiveness of buprenorphine as an analgesic. Another advantage of buprenorphine is that it appears to cause less constipation and dysphoria than other opioids do.

Perhaps buprenorphine’s major advantage over conventional opioids is that it appears to have a ceiling effect on respiratory depression. That means buprenorphine is less likely than conventional opioids to cause someone to stop breathing.

There are several reasons why buprenorphine isn’t prescribed more often as an analgesic. Some people mistakenly believe it is less effective than other opioids at relieving pain for all people. It may not be effective for everyone, but there is a subset of the population for whom it works. In addition, some people believe buprenorphine has a ceiling effect for analgesia that other opioids do not have. However, all opioids appear to have a limit on their ability to relieve pain.

Finally, many people mistakenly feel buprenorphine cannot be used at the same time as other conventional opioids. Conventional opioids can be used in combination with buprenorphine for an added effect. Buprenorphine does not block the effect of concomitant use of conventional opioids.

Because buprenorphine is a schedule III opioid, it is often considered to be “weaker” than schedule II opioids. This reflects a misunderstanding of drug schedule classifications which refer to the drug’s abuse potential, not the drug’s strength as an analgesic.

Summary

All three atypical opioids appear to have safer profiles than conventional opioids. As clinicians try to provide pain relief with the least amount of risk for their patients, these three opioids—tramadol, tapentadol, and buprenorphine—may provide a better solution than conventional opioids.