Opioid therapy is indisputably the mainstay of cancer pain management. However, important issues such as the worldwide variability in the availability and accessibility of opioids, myths and misconceptions about opioid use, and lack of knowledge about prescribing opioids among health care professionals have been pointed out by researchers, clinicians, and several health organizations. In an attempt to improve cancer pain management, guidelines for opioid use were elaborated to assist practitioners in prescribing opioids for the management of cancer-related pain. Recent opioid guidelines were developed based on a systematic assessment of evidence and they are considered one of the best resources to improve knowledge and clinical practice. However, most of the recommendations for cancer pain management included in these guidelines are based on low levels of evidence, which demonstrates that more studies on the use of opioids in pain management are necessary. Moreover, the increased frequency of prescribing opioids for chronic noncancer pain has raised other issues, such as iatrogenic adverse effects, which may also occur in patients with cancer pain on long-term opioid therapy (L-TOT). In this narrative review, we discussed the role of opioid guidelines and recent knowledge regarding the consequences of L-TOT, in particular opioid addiction and deficiencies of the immune and endocrine systems. Finally, we addressed new strategies to strengthen the L-TOT in the management of cancer-related pain among patients in palliative care.