2022年 · 第102卷第39期

Childhood cancer pain is a long-neglected problem. There is a lack of relevant clinical research. Pharmaceutical companies rarely develop preparations separately for this special group during drug development, and often adjust them directly from the treatment plan of adults. At present, the management of childhood cancer-related pain is mainly based on the WHO's 2012 edition of the Guidelines for the Diagnosis and Treatment of Children's Chronic Pain, which deletes the previous recommendation of weak opioids such as tramadol and codeine for children's chronic pain, and emphasizes the direct application of strong opioid morphine when the first-step drugs such as acetaminophen and ibuprofen are not effective. Morphine has a definite analgesic effect and is the "gold standard" for the treatment of acute and chronic severe pain in children. However, for patients who cannot tolerate the adverse reactions of morphine, the current guidelines lack relevant drug recommendations, resulting in a "gap" in pain management. Nalbuphine is a suitable drug to fill this "gap". Nalbuphine is an agonist antagonist of opioid receptors, which agonizes kappa receptors and antagonizes mu receptors. Agonizing kappa receptors makes nalbuphine have a strong analgesic effect, and its antagonistic effect on mu receptors can be used to reverse the adverse reactions of systemic and epidural use of opioids: pruritus, urinary retention or respiratory depression, etc. At the same time, it also leads to its analgesic efficacy is not as good as strong opioids such as morphine, and it has a "ceiling effect", so it is included in the category of intermediate-acting opioids.

Due to the high tolerability of long-term use of methadone, providing adequate pain management is a daunting challenge for this group of patients. Accumulating preclinical and clinical evidence suggests that repeated opioid exposure can catalyze a range of counteranalgesic processes and adverse reactions, including nociceptive sensitization (i.e. hyperalgesia), tolerance, and loss of opioid efficacy. The treatment of acute pain is a particularly intractable problem in patients with methadone maintenance. Previous studies have shown that it is difficult to obtain adequate analgesia even after taking large doses of opioids and non-opioids such as morphine, additional doses of methadone and gabapentin. Hydromorphone, a complete μ-opioid receptor agonist commonly used to treat moderate to severe pain, is considered a promising pharmacotherapeutic strategy to overcome these barriers. In studies of non-opioid tolerance, intravenous administration of 1 to 2 mg hydromorphone was found to provide significant analgesic effects. A recently published buprenorphine-maintained study evaluating the analgesic effect of intravenous hydromorphone provides preliminary evidence that intravenous administration of at least 16 mg of hydromorphone is necessary to maintain clinical pain management in patients with 12 to 16 mg/d sublingual buprenorphine/naloxone. The primary objective of this study was to evaluate the dose effect of hydromorphone compared to placebo in reducing acute pain responses in patients maintaining medium to high doses of oral methadone (80 to 100 mg/d) and to assess concurrent abuse liability for increasing hydromorphone doses, assuming that hydromorphone provides better analgesia than placebo at all time points. This randomized controlled study evaluated the analgesic and abuse propensity effects of escalating doses of acute intravenous hydromorphone versus placebo using a validated experimental pain paradigm, the Quantitative Sensory Test (QST). Patients without chronic pain (n=8) Maintain oral methadone 80~100 mg/d. Participants received 4 intravenous injections over 1 trial day with increasing escalating doses of hydromorphone (32 mg total) or 4 placebo doses over 270 min. Test times are at least 1 week apart. QST and abuse liability measures were performed at baseline and after each injection. There was no statistically significant difference between the hydromorphone and placebo groups in the analgesia index of any QST outcome. Similarly, despite the use of high doses of hydromorphone, there were no statistically significant differences in safety or abuse liability index. The incidence of adverse events was low and the severity of re-reported adverse events was mild.