Author: Bob Kronemyer
The investigational analgesic desmetramadol has the same efficacy and safety as the opiate analgesic tramadol, according to two clinical studies, but desmetramadol does not carry the metabolic shortcomings of tramadol.
Tramadol is believed to be safer than Schedule II opioids because it does not cause clinically significant respiratory depression at either therapeutic or supratherapeutic doses. “Overdoses due to tramadol alone are also rare, so it is an attractive analgesic for many prescribers,” said investigator Lynn R. Webster, MD, the vice president of scientific affairs at PRA Health Sciences in Salt Lake City, and a past president of the American Academy of Pain Medicine.
“The sponsor [Syntrix Biosystems] and I recognize the need for safer medication to treat pain,” said Dr. Webster. “We also recognize that tramadol has inherent liabilities, due to the variable metabolism of cytochrome P450 2D6 [CYP2D6] isoenzymes.”
In addition, because hydrocodone combination products have been changed to Schedule II, many physicians have turned to tramadol as their preferred analgesic, according to Dr. Webster. “As a Schedule IV drug, tramadol can be called in to a pharmacy, which makes it easier for patients and physicians to obtain an analgesic.”
The two pharmacokinetic and analgesic studies of 103 total subjects, which were presented as a poster at the 2019 annual meeting of the American Pain Society (abstract 403), were conducted with tramadol and one of its metabolites: desmetramadol.
The first trial compared desmetramadol, which has both positive and negative enantiomers, with tramadol without CYP inhibition. The second trial used the same two drugs, but included a cytochrome P450 inhibitor: paroxetine. The two double-blind, randomized, placebo-controlled studies concluded that “cytochrome inhibition causes significant reduction in tramadol metabolites and markedly reduces analgesia, whereas cytochrome inhibition has no affect on desmetramadol analgesia,” Dr. Webster said.
Moreover, when tramadol was used as an analgesic, the side effect profile was comparable to desmetramadol. “None of the adverse effects we observed came as a surprise,” Dr. Webster said. “We have also always known that tramadol works like a prodrug and that it has to be metabolized to be effective.”
The FDA recently amended the tramadol label to alert prescribers that there could be unsafe levels of the active metabolite in people who are ultrarapid metabolizers or lack of efficacy in people who are slow metabolizers.
The prevalence of ultrarapid metabolizer genotype ranges from 4% in whites to 11% of those of Middle Eastern descent. “It is estimated that 5% to 10% of the overall population are poor metabolizers, which makes tramadol essentially ineffective in those individuals,” Dr. Webster said.
The clinical impact of the metabolic liability of tramadol is significant. “Abnormal tramadol metabolism affects about one-third of patients,” Dr. Webster said. “In 2017, there were about 41 million tramadol prescriptions dispensed in the United States.”
Dr. Webster noted that the two trials may explain why many clinicians believe tramadol is ineffective or only mildly efficacious. “Eliminating the metabolic problems associated with tramadol may yield a more consistent analgesic profile of a drug that has less abuse potential than Schedule II analgesics,” he said. “Hence, desmetramadol could be an option for treating pain that has formally been limited to drugs with greater abuse potential.”
Mark Holtsman, PharmD, a clinical professor of anesthesiology and pain medicine at the UC (University of California) Davis Medical Center in Sacramento, found the study design interesting but puzzling.
“Pharmacogenetic tests are readily available for CYP2D6,” he said. “I wondered why the investigators did not screen for patients that were CYP2D6 poor metabolizers and then match them with CYP2D6 extensive metabolizers, so that no paroxetine drug effect would impact study results.”
Dr. Holtsman has found only one case report in the literature of a tramadol overdose in a pediatric patient: an ultrarapid metabolizer who also had the comorbid condition of sleep apnea. “Consequently, I believe most clinicians do not worry significantly about tramadol overdose because the metabolite O-desmethyltramadol [M1] is 200 times less potent at the mu-opioid receptor than morphine,” he said.
Dr. Holtsman said the study would not change his clinical practice, because when he desires the pharmacologic effects of a drug like tramadol or desmetramadol, “I simply use venlafaxine or duloxetine, along with a potent opioid [e.g., morphine, oxycodone, hydromorphone] if an opioid is needed.”