Opiate-based painkillers like morphine are important drugs for the treatment of severe, chronic pain. However, they can bring unpleasant side effects such as nausea and constipation. In addition, there is a risk of misuse. An American study shows that low-dose dronabinol (THC) can enhance the pain-relieving effect of hydromorphone. However, higher doses of the cannabinoid increased pain sensitivity, abuse potential and the risk of side effects. Therefore, the adage: less is more applies.
Experimental pain study with 29 healthy test subjects
The double-blind, randomised, placebo-controlled study at Johns Hopkins University involved 29 healthy subjects. A low dose of hydromorphone was selected as the opiate painkiller. The cannabis drug administered was dronabinol, a synthetic form of tetrahydrocannabinol (THC). The research team conducted the trials with five different drug combinations:
- Placebo and placebo
- Hydromorphone and placebo
- Hydromorphone and low dose dronabinol
- Hydromorphone and medium dose dronabinol
- Hydromorphone and high dose dronabinol
The scientific team first conducted research to measure the participants’ perception of pain without the influence of medication. Heat stimuli were used as a laboratory model for acute pain to determine pain threshold and tolerance. Pain threshold is the temperature that is perceived as painful. Pain tolerance is the maximum heat that can be tolerated. In addition, the researchers examined the test subjects for central sensitisation (increased sensitivity to pain). To simulate chronic pain, a capsaicin cream was applied to the skin. Capsaicin is the pungent ingredient in chilli peppers.
The participants then took the medication. The scientists then repeated the measurements and documented any side effects that occurred. In addition, the participants rated the strength of their subjective sensations on a visual analogue scale (VAS) from 0 to 100. They were asked about pleasant and unpleasant effects as well as a “high” feeling. To investigate the potential for abuse, participants were asked whether they enjoyed the effects of the medication and whether they would take the study medication again.
Low THC doses enhance analgesic effect of hydromorphone in acute pain
The scientific study showed that hydromorphone could hardly reduce the experimental acute pain compared to the placebo. The subjects reported an average heat pain threshold of 44.0° Celsius when taking hydromorphone, which was even higher when taking the placebo at 44.7° Celsius. If dronabinol was taken in addition to the opiate, both pain threshold and pain tolerance increased in the acute pain trials. The smallest dose of dronabinol (2.5 mg) showed the strongest pain relief. The pain threshold climbed to 45.6° Celsius, an increase of 1.6° Celsius. The maximum tolerable temperature was also higher at 48.9°Celsius than when taking hydromorphone alone (48.1°Celsius). In contrast, there were no effects in the test model for chronic pain.
However, the potential for abuse also increased. For example, with the combined use of hydromorphone and a low dose of dronabinol, 20.7 percent of the subjects reported their subjective high on the VAS to be over 60, compared to 3.4 percent who took the opiate alone. According to the subjects, more than half (51.7 %) would use the combination of hydromorphone and a medium dose of THC again, compared to 34.5 percent who used only the opiate.
Higher pain sensitivity when opiates are combined with high-dose dronabinol.
However, the two higher cannabinoid doses did not have a better effect against the pain. On the contrary: when taking hydromorphone together with the highest dose of dronabinol, a so-called hyperalgesia, i.e. increased pain sensitivity, was observed. In addition, participants who took a medium or high dose of dronabinol reported more side effects. However, compared to the use of hydromorphone alone, the risk of adverse effects was not significantly increased.
Larger studies with pain patients are needed
The researchers have shown that low doses of tetrahydrocannabinol can increase the pain-relieving effect in people who respond to opioids. This may make it possible to reduce the dose of opioid painkillers, which have many side effects. Since study results generated with healthy people do not necessarily apply to pain patients, the research team concluded that larger studies with affected people are needed. Future research will show how chronic pain patients can best benefit from combined treatment with opiates and THC.
Dunn, K.E., Bergeria, C.L., Huhn, A.S. et al. Within-subject, double-blinded, randomized, and placebo-controlled evaluation of the combined effects of the cannabinoid dronabinol and the opioid hydromorphone in a human laboratory pain model. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01007-4