Given their great efficacy, particularly in the early weeks to months of treatment, opioids remain an important tool in the management of chronic pain. For example, in the Netherlands alone, more than one million inhabitants are prescribed an opioid for treatment of pain [1–3]. The adverse effects that arise during opioid treatment are a matter of great concern. Side effects of physician-supervised opioid consumption include dizziness/lightheadedness, sedation, insomnia, headache, nausea, vomiting, constipation, and drug high. We designed a study that attempts to curb the side effect profile observed during opioid treatment. We do so by combining oxycodone treatment with the inhalation of pharmaceutical-grade cannabis, assuming that the addition of cannabis will reduce the opioid dose and consequently the number of side effects decreases. We are aware that cannabis treatment itself can also come with side effects such as drug high, sedation, and possibly hallucinations and paranoia. However, in this trial, the patient will self-titrate the medication to effect and side effects, and we therefore envision that side effects will remain mild to moderate in severity. We expect patients to curb dosing when AE increase in severity. Moreover, we designed a composite score of occurrences of adverse events that includes both opioid and cannabis side effects. While this seems a reasonable approach, this directly points towards two limitations. First, it may well be that the combination of oxycodone and cannabis leads to a reduction in dose of either component (compared to treatment of either component alone) without changing combined AE profile. Second, we do not score for the severity of each AE component. This is done to simplify data analysis. Additionally, we are aware that patients are able to determine whether an AE is present (such as dizziness) but have difficulty in scoring the severity of such symptoms. Hence, a more practical approach was chosen.

Another limitation of the study is that by combining an opioid with a cannabis product, we might increase the likelihood of abuse and addiction. However, the drug use will be strictly monitored, and hence we expect no drug abuse. Additionally, the chosen dosages are relatively low precluding serious adverse events such as respiratory depression or sedation. In fact, in a recent study (EU trial register, https://www.clinicaltrialsregister.eu, identifier 2021–000083-29), we tested the combination of THC and 20 mg oxycodone in opioid-naïve volunteers and observed absence of enhancement of opioid-induced respiratory depression, and in some subjects even some respiratory stimulation from THC, probably related to its effect at the cannabinoid type 2 receptor in brainstem respiratory networks.

The study is not blinded, and absence of blinding might cause bias that influences study outcome. We reasoned that blinding of the trial would complicate the trial in such a way that it would become impractical to perform. A double dummy approach with placebo tablets (as replacements of oxycodone) and placebo cannabis (as replacement of Bediol®) is theoretically possible but in practice expensive and difficult to manage. We therefore chose the current approach and consider this a proof of concept or exploratory protocol that will lay the basis of future protocols.

An important issue is the risk of diversion of medication. To prevent diversion, the patients were instructed to return all unused medication to the researched on their two-weekly visits. Use of opioid medication other than oxycodone during the study was not allowed. We did not test the subjects for compliance with this restriction. For both items, we rely on the trust between the physician researcher and patient that was created by the close contact between the two. Still, a full-proof strategy to eliminate diversion or additional opioid use is not in our setup.

In conclusion, we will study the effect of oxycodone in combination with inhaled cannabis (the Bediol® variety) relative to either treatment alone, on adverse events during a 6-week treatment course. We are aware that this is a rather complex trial with a large set of outcomes apart from the single primary endpoint, the AE composite score. We believe that this is an important trial, however, that will shed light on our ability to curb opioid treatment for chronic noncancer pain.