NIDA Notes

In Animals, Opioid Combination Shows Promise for Safer Pain Relief

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By Stacey C. Tobin, Ph.D., ELS, NIDA Notes Contributing Writer

This study found that:

  • In rats, co-administration with nalfurafine reduced the dose of oxycodone required to lower pain responses in models of human chronic pain.
  • The combination treatment generated less abuse liability and produced less respiratory depression than oxycodone alone.

Spurred by the epidemic of opioid overdoses and deaths in the United States, researchers are seeking new formulations of opioid pain relievers that will reduce the medications’ potential for misuse and overdose without compromising their analgesic effectiveness. In one such effort, NIDA-funded researchers recently tested a combination of the prescription analgesic oxycodone and nalfurafine, which is used in Japan to treat itching associated with hemodialysis and chronic liver disease.

The two medications act on different opioid receptors in the brain. Oxycodone and most other prescription opioid analgesics stimulate mu opioid receptors, suppressing pain but also causing rewarding effects that confer risk for misuse and addiction. Mu receptor agonists also suppress breathing, making overdoses potentially fatal.

Figure 1. Nalfurafine Enhances Oxycodone’s Analgesic Potency Oxycodone/nalfurafine mixtures produced similar reductions in rats’ pain responses (percentage maximum possible effect) with less oxycodone. An 18:1 oxycodone/nalfurafine mixture reduced the amount of oxycodone needed for a similar amount of pain relief by roughly a factor of 10. See full text description at end of article.

In contrast, nalfurafine stimulates kappa opioid receptors. Kappa receptor agonists can reduce the rewarding effects of mu agonists without altering their ability to relieve pain. They are also less likely than mu agonists to depress the respiratory system. However, they carry other side effects, including creating feelings of uneasiness and sadness (dysphoria) and even psychosis.

In the new study, Drs. E. Andrew Townsend and Kevin Freeman from the University of Mississippi Medical Center in Jackson, along with colleagues from several institutions, administered various combinations of oxycodone/nalfurafine to rats to determine if they might enhance oxycodone’s positive effects and reduce its negative effects. They examined three key endpoints:

  • Self-administration of oxycodone (a measure of abuse potential)
  • Pain relief in response to heat
  • Respiratory depression.
Figure 2. Oxycodone/Nalfurafine Produces Less Risk for Abuse and Respiratory Depression Than Oxycodone Alone Rats exhibited less motivation to self-administer oxycodone (left panel) and less respiratory depression (right panel) when treated with oxycodone/nalfurafine than with oxycodone alone. The greatest effect was observed with an oxycodone/nalfurafine ratio of 18:1. See full text description at end of article.

The analyses showed that combining oxycodone with nalfurafine at a ratio of 18:1 greatly reduced the dose of oxycodone required to relieve pain (see Figure 1). Rats did not self-administer significantly more of the combination than they did saline, suggesting that it did not produce the rewarding sensations that can lead to abuse and addiction. The researchers also observed no signs of respiratory depression from the combination at this ratio (see Figure 2). Higher oxycodone/nalfurafine ratios also enhanced oxycodone’s pain-killing effects, but showed evidence of abuse potential and/or respiratory depression.

These findings suggest that combined mu/kappa opioid receptor agonist medications may be able to save lives by relieving pain while limiting potentially fatal side effects. When asked about the anticipated benefits of this work, Dr. Townsend asserts, “The majority of illicit opioid users begin their path to addiction by misusing prescription opioid medications. We feel that if more steps are taken to reduce the recreational appeal of these medications, fewer people will progress from pain management to opioid use disorder.” Future studies will need to examine whether oxycodone/nalfurafine combinations have similar effects in humans.

The study was supported by NIH grant DA039167.

Text Description of Figure 1

The line graph shows how the addition of nalfurafine enhances the pain-relieving effects of oxycodone. The horizontal x-axis shows the oxycodone dose in mg/kg body weight, with marks indicating 0.1 mg/kg, 0.32 mg/kg, 1.0 mg/kg, 3.2 mg/kg, and 10 mg/kg. The vertical y-axis shows the percentage of maximum possible effect (MPE) from 0% to 100%. For oxycodone alone, indicated by the yellow circles, a dose of 1 mg/kg achieved about 10% MPE, a dose of 3.2 mg/kg achieved about 50% MPE, and a dose of 5.6 mg/kg achieved about 85% MPE. For a combination of oxycodone/nalfurafine at a ratio of 175:1, indicated by the red diamonds, a dose of 1 mg/kg achieved about 10% MPE, and a dose of 3.2 mg/kg achieved about 95% MPE. For a combination of oxycodone and nalfurafine at a ratio of 56:1, indicated by the purple triangles, a dose of 0.32 mg/kg achieved about 10% MPE, a dose of 1.0 mg/kg achieved about 40% MPE, and a dose of 3.2 mg/kg achieved about 100% MPE. For a combination of oxycodone and nalfurafine at a ratio of 18:1, indicated by the blue squares, a dose of 0.1 mg/kg achieved about 0% MPE, a dose of 0.32 mg/kg achieved about 35% MPE, and a dose of 1.0 mg/kg achieved about 100% MPE.

Text Description of Figure 2

The bar charts show how the addition of nalfurafine to oxycodone reduces the risk for abuse and respiratory depression associated with oxycodone. On the left panel, the horizontal x-axis shows the medications used for the test and the vertical y-axis shows the number of self-administered oxycodone injections, which represent abuse liability, from 0 to 30. Animals that received only saline (white bar) self-administered about 9 oxycodone injections, whereas animals that received only oxycodone (yellow bar) self-administered about 23 oxycodone injections. Animals that received oxycodone/nalfurafine at a ratio of 175:1 (red bar) self-administered about 18 oxycodone injections, animals that received oxycodone/nalfurafine at a ratio of 56:1 (purple bar) self-administered about 16 oxycodone injections, and animals that received oxycodone/nalfurafine at a ratio of 18:1 (blue bar) self-administered about 11 oxycodone injections.

On the right panel, the horizontal x-axis shows the medications used for the test and the vertical y-axis shows the pulmonary ventilation on a scale from -60 to +40, with negative numbers indicating respiratory depression. Animals that received only saline (white bar) had a pulmonary ventilation of about +4, whereas animals that received only oxycodone (yellow bar) had a pulmonary ventilation of about -40 and those that received only nalfurafine (green bar) had a pulmonary ventilation of about -17. Animals that received oxycodone/nalfurafine at a ratio of 175:1 (red bar) had a pulmonary ventilation of about -35, animals that received oxycodone/nalfurafine at a ratio of 56:1 (purple bar) had a pulmonary ventilation of about -27, and animals that received oxycodone/nalfurafine at a ratio of 18:1 (blue bar) had a pulmonary ventilation of about -10.

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