Tramadol: An Emerging Drug of Abuse

Written By: Timothy C. Fagan, MD, FACP and Frederick J. Kogan, PhD, MD, FACG, AGAF

Introduction

Since the mid-1990s, physicians, pharmaceutical corporations and advocacy organizations have promoted the increased use of opioids, including synthetic derivatives, for treatment of acute and chronic pain.  As a result, there has been exponential growth in opioid prescribing in the last 25 years in the United States and other Western developed countries.  Opioids carry significant risks of side effects and complications, which include misuse, abuse, dependence and death.

Increased prescription rates, economic damage, opioid abuse, and overdose deaths have brought these topics to the forefront of national attention and discussion¹.  Unfortunately, pharmaceutical corporations, regulatory agencies, and physicians have lost sight of a basic pharmacological principle: The value of drug therapy must be judged not only on the immediate efficacy and side effects, but also on the long-term effects, including the quality of the patient’s life.

Opioids vs Opiates

Opiates are compounds structurally related to products found in opium, which is derived from the resin of the opium poppy².  Opiates include morphine, codeine, thebaine, and semi-synthetic derivatives, such as oxycodone and hydrocodone.  Opioids are any compounds that have the functional and pharmacological properties of an opiate.  Opioids include all opiates, as well as synthetic derivatives, such as methadone, fentanyl, carfentanil and tramadol.  Endogenous opioids, or endorphins, are produced in the body.  There are 3 separate opioid receptors. The mu receptor(MOR) is the receptor primarily responsible for pain relief.

Adverse effects of opioids include nausea, urticaria, bronchospasm, sedation, constipation, urinary retention, hypotension and respiratory depression.  In opioid overdose situations, these adverse effects are exaggerated.  When death occurs, it is almost always due to respiratory depression.

Tramadol

Tramadol is a structural analog of codeine².  Tramadol and its primary metabolite, o-desmethyltramadol (M1), are MOR agonists.  M1 binds much more tightly to the MOR, and therefore is a much more potent agonist than tramadol itself.  In addition, tramadol inhibits neuronal reuptake of serotonin and norepinephrine in vitro, which makes it a Serotonin, Norepinephrine Reuptake Inhibitor (SNRI), similar to venlafaxine (Effexor) and duloxetine (Cymbalta).  This may contribute to its analgesic effect and may partially counteract its sedative effect.  Tramadol is equipotent with morphine for mild to moderate pain, but, like codeine, it is less effective than morphine for severe pain.  Oral bioavailability of tramadol is about 75%. The half-lives of tramadol and M1 are 6-7 hours. M1 is formed by CYP2D6, and is therefore subject to interactions with other drugs metabolized by CYP2D6.  Less than 10% of Caucasians lack CYP2D6 and do not produce M1, resulting in much less opioid effect of tramadol.  Conversion of tramadol to M1 varies in other ethnic groups. Tramadol is primarily excreted in the urine as parent drug and metabolites. This leads to increased plasma and tissue concentrations in patients with decreased renal function.  The decreased hepatic function may result in less conversion to M1, but also reduced clearance of tramadol and M1 from the body.  For these reasons, ethnicity, renal function, hepatic function and drug interactions, the therapeutic and adverse effects of tramadol vary widely from person to person.

Tramadol was originally introduced and promoted as a nonscheduled drug in April 1995, based on the assumption that the risk of abuse was sufficiently low to warrant non-scheduled designation. Symptoms of withdrawal from tramadol include anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and hallucinations.  These are similar to symptoms of withdrawal from other opioids.

Tramadol is widely available internationally.  In many countries, tramadol is not a controlled substance.  In Canada, it was only added to the same schedule as other opioids in 2014.  In the US, tramadol was added to Schedule IV in 2014.  This is the same schedule as benzodiazepines.  Schedule IV regulations are less strict than Schedule III or II, where all other opioids are listed.

TRAMADOL ABUSE

Opioid abuse is epidemic in the US.  From 2000-2016 the death rate for synthetic opioids except for methadone, including fentanyl and tramadol, has increased more than 20-fold, more than for any other subgroup of opioids, See Table 1.  In the US, deaths from overdoses of all drugs rose from 17,415 in 2000, 6.2/100,000 population, to 63,632, 19.8/100,000 in 2016, a 219% increase in 16 years³.  In Arizona in 2016, the rate was 20.3 deaths per 100,000 population, slightly above average for the country.  In 2015, the overdose death rate for males was 20.8, almost twice the 11.8 rate in females.

Death rates for tramadol alone are difficult to find, since it is usually grouped with other synthetic opioids, such as fentanyl.  However, the US Substance Abuse and Mental Health Services Administration (SAMHSA) reported that from 2005-2011 Emergency Department visits for tramadol-related misuse or abuse increased 250% from 6,255 to 21,649 in this 6 year period⁴, see Figure 1. Visits by males increased from 2,333 to 9,411 and visits by females increased from 3,922 to 12,238.  This higher rate of ED visits in females compared to males, is the reverse from the overall higher death rate for males from all opioids combined.  The greatest increase in ED visits for tramadol-related misuse or abuse was 481% in patients aged 55 and older, probably consistent with the number of prescriptions in this age group.  Overall, 38% of ED visits for tramadol-related misuse or abuse resulted in hospitalization or transfer to another medical facility.

Table 1   US Age-Adjusted Opioid Overdose Death Rates

Adapted from Reference 4

Conclusion

Tramadol and M1 are clearly MORs with adverse effects and symptoms of overdose similar to those of other opioids.  Death rates in tramadol overdoses are significant, and the rate of increase in tramadol overdoses is similar to that with other opioids.  Tramadol is clearly addictive.  In light of these facts, physicians should exercise the same caution when prescribing tramadol as they would with Schedule II and III drugs.

References

1. Binbaum, HC, et al. Societal Costs of Prescription Opioid Abuse, Dependence and Misuse in the United States. Pain Med 12; 657-667, 2011.
2. TL Yaksh and MS Wallace. Opioids, Analgesia and Pain Management, in Goodman and Gilman’s Pharmacological Basis of Therapeutics, Twelfth Edition, 2011
3. H Hedegaard, M Warner, AM Minino. Drug Overdose Deaths in the United States, 1999-2016, Data Brief 294, December 2017. cdc,gov/nchs/products/databriefs/db294.htm
4. DM Bush, The DAWN Report: Emergency Department Visits for Drug Misuse or Abuse Involving the Pain Medication Tramadol, May 14, 2015. samhsa.gov/data/sites/default/files/report_1966/Short Report-1966.html