BOSTON—Codeine may induce hyperalgesia and allodynia to a similar extent as morphine does, according to research presented at the 2013 International Headache Congress. Compared with morphine, codeine appears to be a less effective analgesic, but it may cause greater glial reactivity and equal changes in pain sensitivity, investigators reported.
Male mice that underwent chronic constriction injury surgery subsequently had allodynia and hyperalgesia. Mice treated with codeine or morphine developed hyperalgesia earlier if they had undergone the surgery than if they had not had the surgery. This result is “consistent with a glial-mediated hypothesis of pain facilitation,” said Jacinta Johnson, a doctoral candidate at the University of Adelaide in Australia. Treatment with ibudilast reversed the opioid-induced allodynia and attenuated glial reactivity in the trigeminal ganglion.
Studying Pain Sensitivity in Mice
Codeine is cheaper than triptans, and many patients use it to manage their headaches. For these reasons, Ms. Johnson and colleagues conducted mouse studies to determine whether codeine induces hyperalgesia and allodynia to the same extent that morphine does. Male mice were randomized to morning and evening treatments with 21 mg/kg of codeine, 20 mg/kg of morphine, or saline for four days. Mice underwent the von Frey and hot plate tests on days 1, 3, and 5. Tissue samples were collected on day 5. The researchers also evaluated the levels of analgesia provided by codeine and morphine using a hot plate test in a separate mouse cohort.
To test the glial-mediated hypothesis of pain facilitation, another group of mice underwent von Frey testing at baseline and subsequently received chronic constriction injury surgery. These mice underwent von Frey testing on days 3, 7, and 11 after surgery.
A fourth group of mice was randomized to morning and evening treatments with 21 mg/kg of codeine and 15 mg/kg of ibudilast, 21 mg/kg of codeine and vehicle, 20 mg/kg of morphine and 15 mg/kg of ibudilast, or 20 mg/kg of morphine and vehicle. The mice underwent von Frey and hot plate tests on days 1, 3, and 5. Tissue samples were collected on day 5.
Codeine and Morphine Reduced Hot Plate Latency
Codeine and morphine reduced hot plate latency to similar extents at day 5, compared with saline. The drugs also reduced the number of paw nonwithdrawals at days 3 and 5, compared with baseline. Following surgery, codeine and morphine reduced hot plate latency at days 3 and 5, compared with saline. The drugs also reduced the number of paw nonwithdrawals at days 3 and 5 after surgery, compared with baseline.
“As codeine possesses lesser opioid analgesic efficacy than morphine, but causes greater glial reactivity and equal changes in pain sensitivity, codeine cannot be considered to have only traditional opioid pharmacology,” said Ms. Johnson and her research colleagues. “Our data suggest [that] codeine may be particularly liable to produce opioid-induced hyperalgesia,” the researchers said. “High glial reactivity in the trigeminal ganglion further supports caution regarding chronic codeine use in pain and headache,” they concluded.
—Erik Greb
Senior Associate Editor