Opioid analgesics are widely accepted as first-line treatment for moderate to severe cancer pain: while their use in patients with non-cancer pain syndromes has increased substantially over the last years. However, opioid analgesia produces numerous adverse effects. These effects have a negative impact on patient’s quality of life, may impair adherence to treatment and finally limitate opioid use. Most of opioid-related side effects are well established, i.e. constipation, nausea and vomiting, pruritus, respiratory depression or cognitive impairment, while others, i.e. opioid-induced immunosuppression, hypogonadism or opioid-induced hyperalgesia have gained attention only in the past few years. Beside the fact that some of them are potentially life-threatening, like respiratory depression, the potential risk of iatrogenic addiction still remains the most significant barrier to their use and frequently leads to pain undertreatment. The aim of this review is to present opioid-related side effects, the underlying mechanisms and the proposed treatment modalities, focusing on the existing evidence.